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Textbook of Benign Prostatic Hyperplasia 2Nd Ed. Kirby, R. S. Informa Healthcare 190186555X 9781901865554 9780203640449 English Prostate--Hypertrophy, Prostate--Hypertrophy-Treatment, Prostatic Hyperplasia--diagnosis, Prostatic Hyperplasia--therapy, Adrenergic alpha-Antagonists-therapeutic use. 2005 RC899.T49 2005eb 616.6/5 Prostate--Hypertrophy, Prostate--Hypertrophy-Treatment, Prostatic Hyperplasia--diagnosis, Prostatic Hyperplasia--therapy, Adrenergic alpha-Antagonists-therapeutic use.
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Page i Second Edition TEXTBOOK OF BENIGN PROSTATIC HYPERPLASIA
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Textbook of Benign Prostatic Hyperplasia 2Nd Ed. Kirby, R. S. Informa Healthcare 190186555X 9781901865554 9780203640449 English Prostate--Hypertrophy, Prostate--Hypertrophy-Treatment, Prostatic Hyperplasia--diagnosis, Prostatic Hyperplasia--therapy, Adrenergic alpha-Antagonists-therapeutic use. 2005 RC899.T49 2005eb 616.6/5 Prostate--Hypertrophy, Prostate--Hypertrophy-Treatment, Prostatic Hyperplasia--diagnosis, Prostatic Hyperplasia--therapy, Adrenergic alpha-Antagonists-therapeutic use.
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Page iii Second Edition TEXTBOOK OF BENIGN PROSTATIC HYPERPLASIA Edited by Roger S Kirby MA MD FRCS (Urol) FEBU Visiting Professor of Urology St. George’s Hospital London, UK John D McConnell MD Professor of Urology University of Texas Southwestern Medical Center Dallas, Texas, USA John M Fitzpatrick MCh FRCSI FC Urol (SA) FRCSGlas FRCS Consultant Urologist and Professor of Surgery Mater Misericordiae Hospital and University College Dublin Dublin, Ireland Claus G Roehrborn MD Professor of Urology University of Texas Southwestern Medical Center Dallas, Texas, USA Peter Boyle PhD Director, Division of Epidemiology and Biostatistics European Institute of Oncology, Milan, Italy
LONDON AND NEW YORK A MARTIN DUNITZ BOOK
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Page iv © 2005 Taylor & Francis, an imprint of the Taylor & Francis Group First published in the United Kingdom in 2005 by Taylor & Francis, an imprint of the Taylor & Francis Group, 2 Park Square, Milton Park Abingdon, Oxon OX14 4RN, UK Tel.: +44 (0) 1235 828600 Fax.: +44 (0) 1235 829000 Website: www.tandf.co.uk This edition published in the Taylor & Francis e-Library, 2005. To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to www.eBookstore.tandf.co.uk. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. British Library Cataloguing in Publication Data Data available on application Library of Congress Cataloging-in-Publication Data Data available on application ISBN 0-203-64044-6 Master e-book ISBN ISBN 0-203-69366-3 (OEB Format) ISBN 1-90186-555-X (Print Edition) Distributed in North and South America by Taylor & Francis 2000 NW Corporate Blvd Boca Raton, FL 33431, USA Within Continental USA Tel.: 800 272 7737; Fax.: 800 374 3401 Outside Continental USA Tel.: 561 994 0555; Fax.: 561 361 6018 E-mail:
[email protected] Distributed in the rest of the world by Thomson Publishing Services Cheriton House North Way Andover, Hampshire SP10 5BE, UK Tel.: +44 (0) 1264 332424 E-mail:
[email protected] Composition by Parthenon Publishing
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Page v Contents Preface Foreword List of Contributors
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viii ix xi
3
11
29
69
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Section I: Basic Science
1. Macro-anatomy of the prostate J S Dixon, J A Gosling 2. Embryology and development of the prostate E Shapiro, M S Steiner 3. Molecular control of prostatic growth A Turkes, K Griffiths 4. Molecular aspects of benign prostatic hyperplasia M R Freeman, M E Gleave, L W K Chung 5. Human prostatic adrenoceptors K-E Andersson, M G Wyllie 6. The pathology of benign prostatic hyperplasia D G Bostwick 7. Bladder responses to obstruction G E Lemack, J D McConnell 8. Molecular genetics of benign prostatic hyperplasia S F Shariat, E I Canto, K M Slawin
Section II: Epidemiology
9. Measuring and assessing BPH in population groups M J Barry 10. Descriptive epidemiology of benign prostatic hyperplasia H A Guess, C J Girman 11. Etiology of benign prostatic hyperplasia G S Sonke, C A Mochtar, L A L M Kiemeney 12. Epidemiology of acute urinary retention K Thomas, P Boyle 13. Natural history of benign prostatic hyperplasia J Shah
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Page vi
Section III: Evaluation
14. Evaluating symptoms and functional status 201 G S Adey, M P O’Leary, M J Barry 15. Screening for prostate cancer in patients with benign prostatic hyperplasia 211 D E Drachenberg, M K Brawer 16. Flow rate and postvoid residual issues 227 E P Arnold 17. Urodynamics and benign prostatic hyperplasia 241 A E Te, E F Ikeguchi, J Choi, S A Kaplan 18. Imaging and benign prostatic hyperplasia 255 D Rickards 19. Prostatic needle biopsy in men with BPH: histopathologic interpretation and clinical significance 267 M R Feneley, S R J Bott 20. Neurologic and neurophysiologic assessment 279 C J Fowler, K J O’Malley, R S Kirby
Section IV: Medical Treatment
21. Medical management—watchful waiting P Hegarty, J M Fitzpatrick, R C Bruskewitz 22. The placebo effect in the treatment of benign prostatic hyperplasia C G Roehrborn 23. Dutasteride in the treatment of the BPH patient J D McConnell, C G Roehrborn 24. Finasteride in the treatment of benign prostatic hyperplasia J D McConnell 25. Combination therapy in the treatment of BPH C G Roehrborn 26. The differential effects of adrenoceptor antagonists on prostate tissue growth N Kyprianou 27. Terazosin in the treatment of obstruction of the lower urinary tract M Brawer, J M Fitzpatrick 28. Doxazosin in the treatment of benign prostatic hyperplasia R S Kirby 29. Alfuzosin A Jardin 30. Tamsulosin C R Chapple
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287 295 319 327 339 351 357 365 377 391
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Page vii 31. Phytotherapeutic agents in the treatment of LUTS and BPH K Dreikorn, J M Fitzpatrick 32. Uroselectivity revisited K-E Andersson, M G Wyllie
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Section V: Surgical/Interventional Options
33. Surgical interventions for BPH J Shah, C G Roehrborn 34. Transurethral laser prostatectomy B S Stein 35. Transurethral needle ablation (TUNA) for treatment of benign prostatic hyperplasia C C Schulman, A R Zlotta 36. Interstitial laser therapy for benign prostatic hyperplasia T McNicholas 37. Transurethral microwave thermotherapy S St Clair Carter, A Tubaro 38. Temporary stents J Nordling
441 483 495 507 519 529
Section VI: Shared Care
39. The impact of BPH on sexual function C C Carson Index
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Page viii Preface Unlikely as it seems from our perspective, it is 8 years since the first edition of the Textbook of Benign Prostatic Hyperplasia was first published. Rather a lot has happened in this increasingly important disease area since then. The realization has dawned that more than half of all men beyond middle age—and more and more of us now fall into this category—suffer some quality of life impairment due to this highly prevalent disease. Moreover, an important link between lower urinary tract symptoms (LUTS) due to BPH and sexual dysfunction has recently been established. Basic science has advanced considerably and we now are beginning to have a clearer understanding of the molecular mechanisms that underlie the abnormal growth patterns that characterize this common medical problem. Methods of diagnosis have been refined and invasive testing, such as urodynamics and cystoscopy, are now much less frequently employed. Medical therapy is increasingly employed and the recently reported MTOPS study suggests that the combination of a 5α-reductase inhibitor and an αblocker provides the optimum means of relieving symptoms and preventing disease progression. Surgery has also evolved dramatically. Laser prostatectomy using the holmium laser, and a host of other minimally invasive technologies, are now seriously challenging standard transurethral resection (TURP) as the gold standard intervention for this disease. For all of these reasons a second edition of this book was clearly overdue. We would like to thank all the contributors to this book for the superb state-of-the-art overviews that they have provided. We would also especially like to thank the outstanding publishing team including Alan Burgess, Martin Lister, Karen Kennedy and Kath Burrow for the enthusiasm and sheer hard work that have turned this project into reality. Roger S Kirby John D McConnell John M Fitzpatrick Claus G Roehrborn Peter Boyle
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Page ix Foreword The editors of the second edition of Textbook of Benign Prostatic Hyperplasia have assembled a thoughtful group of authors who are experts in the field of benign prostatic hyperplasia and have produced the most comprehensive book on the topic that has been published. The chapters are concise, readable yet thorough, addressing all aspects of BPH. Particularly engaging are the chapters on medical management, where an expert who has personal experience with the drug addresses each specific treatment modality discussed. In a similar fashion, the surgical intervention options are discussed in detail. Moreover, the clinical chapters guide the clinician through appropriate diagnostic strategies, the limitations of clinical trials and then are filled with evidence-based data, citing where appropriate studies are missing. The basic science chapters are timely and review in a logical sequence all aspects of the development of the prostate, its innervation, and the response of the bladder to obstruction. These chapters should guide urologic investigators to the development of new strategies for both the prevention and treatment of BPH. Taken altogether, the text is a readable compendium on BPH, which will be enjoyed by all urologists, and others interested in the topic. E Darracott Vaughan Jr, MD
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Page xi List of Contributors Gregory S Adey MD Clinical Fellow in Surgery/Urology Harvard Medical School Brigham and Women’s Hospital Boston, MA 02115, USA Karl-Erik Andersson Department of Clinical Pharmacology Lund University Hospital 221 85 Lund, Sweden Edwin P Arnold MB ChB PhD FRCS FRACS Associate Professor, Department of Urology Christchurch Hospital Private Bag 4710 Christchurch, New Zealand Michael J Barry MD Chief, General Medicine Unit Massachusetts General Hospital Associate Professor of Medicine, Harvard Medical School 50 Staniford Street, 9th Floor Boston, MA 02114, USA Simon R J Bott Research Registrar, Institute of Urology and Nephrology UCL UCL Hospitals Trust Mortimer Street London W1T 3AA, UK David G Bostwick MD MBA Medical Director, Bostwick Laboratories 2807 N.Parham Road Richmond, VA 23294, USA Peter Boyle PhD Director, Division of Epidemiology and Biostatistics European Institute of Oncology via Ripamonti 435 20141 Milan, Italy Michael K Brawer MD Director of Northwest Prostate Institute Northwest Hospital Seattle, WA 98133, USA Reginald C Bruskewitz MD Professor of Surgery, Department of Surgery Division of Urology Clinical Science Center 600 Highland Avenue Madison, WI 53792, USA Eduardo I Canto Scott Department of Urology Baylor College of Medicine 6560 Fannin, Suite 2100 Houston, TX 77030, USA Cully C Carson MD FACS Rhodes Distinguished Professor Chief of Urology University of North Carolina 2140 Bioinformatics Building Chapel Hill, NC 27599–7235, USA Christopher R Chapple MD FRCS(Urol) FEBU file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_xi.html[09.07.2009 11:51:14]
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Consultant Urological Surgeon Department of Urology Royal Hallamshire Hospital Glossop Road Sheffield S10 2JF, UK James Choi MD College of Physicians and Surgeons Columbia University Columbia Presbyterian Medical Center 622 West 168th Street New York, NY 10004, USA
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Page xii Leland W K Chung PhD Professor of Urology and Cell Biology The University of Virgina Health System Molecular Urology and Therapeutics Program Box 422 Charlottesville, VA 22908, USA John S Dixon PhD Retired Darrel E Drachenberg MD FRCSC Urologic Oncologist, Assistant Professor of Surgery, Section of Urology University of Manitoba, St Boniface General Hospital 409 Tache Avenue, Room Z 3036 Winnipeg MB, R2H 2A6, Canada Kurt Dreikorn Urology Clinic St. Jurgen Str. 28205 Bremen, Germany Mark R Feneley MD FRCS(Eng) FRCS(Urol) Senior Lecturer, Institute of Urology and Nephrology University College London 48 Riding House Street London W1W 7EY, UK John M Fitzpatrick MCh FRCSI FC Urol (SA) FRCSGlas FRCS Consultant Urologist and Professor of Surgery Mater Misericordiae Hospital and University College Dublin 47 Eccles Street Dublin 7, Ireland Clare J Fowler FRCP Professor of Uro-Neurology, Institute of Neurology, UCL and National Hospital for Neurology and Neurosurgery Queen Square London WC1N 3BG, UK Michael R Freeman PhD Director, Urology Research, Children’s Hospital Boston Associate Professor, Department of Surgery Harvard Medical School Enders Research Laboratories, Rm. 1161 300 Longwood Avenue Boston, MA 02115, USA Cynthia J Girman Senior Director, Epidemiology Department Merck Research Laboratories 10 Sentry Parkway Blue Bell, PA 19422, USA Martin E Gleave MD FRCSC Associate Professor of Surgery University of British Columbia Division of Urology Vancouver Hospital and Health Sciences Center, D-9 2733 Heather Street Vancouver, BC, V5Z 3J5, Canada John A Gosling MB CHB MD FRCS Professor of Anatomy Division of Anatomy Stanford University CCSR Building file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_xii.html[09.07.2009 11:51:15]
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269 Campus Drive Stanford, CA 94305–5140, USA Keith Griffiths BSc MSc PhD DSc Formerly Tenovus Cancer Research Centre University of Wales College of Medicine Heath Park Cardiff CF14 4XX, Wales, UK Harry A Guess MD PhD Professor, Department of Epidemiology McGavran-Greenberg Hall, Room 2105B School of Public Health University of North Carolina at Chapel Hill Chapel Hill, NC 27599–7435, USA P Hegarty University College Hospital Galway, Ireland Edward F Ikeguchi Department of Urology College of Physicians and Surgeons Columbia University New York, NY 10004, USA
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Page xiii Alain Jardin MD Chef du Service D’Urologie Université Paris Sud Centre Hospitalier de Bicêtre Secteur P.Broca 78 rue Général Leclerc 94275 Le Kremlin-Bicêtre, Cedex, France Steven A Kaplan MD Herbert Irving Associate Professor of Urology J.Bentley Squier Urological Clinic College of Physicians and Surgeons, Columbia University Columbia Presbyterian Medical Center 622 West 168th Street New York, NY 10004, USA Lambertus A L M Kiemeney PhD Professor of Cancer Epidemiology Radboud University Medical Center PO Box 9001 NL-6500 HB, Nijmegen, The Netherlands Roger S Kirby MA MD FRCS (Urol) FEBU Professor of Urology 145 Harley Street, London W1G 6BJ, UK Natasha Kyprianou MD PhD Professor, Division of Urology Department of Surgery University of Kentucky Medical Center 800 Rose Street Lexington, KY 40536, USA Gary E Lemack MD Associate Professor of Urology Director of Neurourology University of Texas Southwestern Medical Centre 5323 Harry Hines Boulevard, J8.122 Dallas, TX 75390–9110, USA John D McConnell MD Professor of Urology, Department of Urology University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard, B11.300 Dallas, TX 75390–9131, USA Tom McNicholas MBBS FRCS FEBU Consultant Urological Surgeon The Lister Hospital Corey’s Mill Lane Stevenage, SG1 4AB, UK Chaidir A Mochtar MD Urologist, Department of Urology Academic Medical Center 1100 DE Amsterdam, The Netherlands Jørgen Nordling DrMedSci FEBU Professor of Urology, Department of Urology, H 123 Herlev Hospital University of Copenhagen 2730 Herlev, Denmark Michael P O’Leary MD MPH Associate Professor of Surgery, Harvard Medical School Senior Surgeon, Division of Urology Brigham and Women’s Hospital file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_xiii.html[09.07.2009 11:51:15]
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Boston, MA 02115, USA Kiaran J O’Malley MCh FRCS (Urol) FEBU Fellow in the Department of Uro-Neurology National Hospital for Neurology and Neurosurgery, and Fellow at the Institute of Urology Queen Square London WC1N 3BG, UK David Rickards FRCR, FFRDSA Consultant Uroradiologist University College Hospitals London The Middlesex Hospital London W1N 8AA, UK Claus G Roehrborn MD Professor and Chairman, Department of Urology The University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard, J8.142 Dallas, TX 75390–9110, USA Claude C Schulman MD PhD Professor of Urology, Department of Urology Erasme Hospital University Clinics of Brussels 808 rue route de Lennik 1070 Brussels, Belgium
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Page xiv Jyoti Shah BSc MRCS MD DHMSA Urology SpR Kingston Hospital Galsworthy Road Kingston upon Thames, Surrey KT2 7QB, UK Ellen Shapiro MD Department of Urology New York University School of Medicine 150 E. 32nd Street, 2nd First Avenue New York, NY 10016, USA Shahrokh F Shariat Scott Department of Urology Baylor College of Medicine 6560 Fannin, Suite 2100 Houston, TX 77030, USA Kevin M Slawin MD Scott Department of Urology Baylor College of Medicine 6560 Fannin, Suite 2100 Houston, TX 77030, USA Gabe S Sonke MD PhD Resident in Internal Medicine Department of Internal Medicine University Medical Centre Utrecht 3508 GA Utrecht, The Netherlands Simon St Clair Carter FRCS Imperial College School of Medicine London University and Department of Urology Hammersmith Hospitals Trust London W12 0HS, UK Barry S Stein MD Professor and Chief, Division of Urology Brown University School of Medicine 2 Dudley Street, Suite 175–185 Providence, RI 02912, USA Mitchell S Steiner MD Department of Urology The University of Tennessee College of Medicine Memphis, TN 38163, USA Alexis E Te MD Associate Professor of Urology Director of the Prostate Center and Urodynamics Weill Medical College of Cornell University 1300 York Avenue, F918 New York, NY 10021, USA Kay Thomas Urology Registrar, Urology Department St George’s Hospital London SW17 0QT, UK Andrea Tubaro Department of Urology 2nd School of Medicine, “La Sapienza” University, and St Andrea Hospital 00189 Rome, Italy Atilla Turkes BSc, MSc, PhD Principal Clinical Scientist Department of Medical Biochemistry and Immunology file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_xiv.html[09.07.2009 11:51:16]
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University Hospital of Wales Heath Park Cardiff CF14 4XW, Wales, UK Michael G Wyllie BSc, PhD Pfizer Inc 235 East 42nd Street New York, NY 10017–5755, USA Alexandre R Zlotta MD Department of Urology University Clinics of Brussels Erasme Hospital 808 rue route de Lennik 1070 Brussels, Belgium
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Page 1 I Basic Science
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Page 3 1 Macro-anatomy of the prostate J S Dixon J A Gosling Introduction The prostate is shaped like an inverted pyramid and lies between the urinary bladder and the pelvic floor (Fig. 1.1). It is a fibromuscular glandular organ that surrounds the prostatic urethra. The prostate has a base and an apex, and anterior, posterior, and inferolateral surfaces. The base is the upper surface adjacent to the preprostatic urethra and bladder neck while the blunt apex is the lowest part. The anterior surface limits the retropubic space posteriorly and is connected inferiorly to the pubic bones by the puboprostatic ligaments. The inferolateral surfaces are clasped by the levator prostatae parts of the levator ani muscle, while the posterior surface lies in front of the lower rectum and is separated from it by the rectovesical fascia. The ejaculatory ducts pierce the posterior surface just below the bladder and pass obliquely through the gland for about 2 cm to open separately into the prostatic urethra about half way along its length on the verumontanum. A thin layer of connective tissue at the periphery of the prostate forms a ‘true’ capsule, outside which is a condensation of pelvic fascia forming the so-called ‘false’ capsule. A plexus of veins lies between these two capsules. Blood supply and lymphatic drainage The main arterial supply to the prostate gland is from the prostatic branch of the inferior vesical artery, with some small branches from the middle rectal internal pudendal vessels passing to the lower part. Occasionally, the middle rectal artery provides the major supply. The veins from the prostate gland form the prostatic venous plexus situated between the true capsule of the gland and the outer fibrous sheath. The lymph vessels from the prostate gland drain into the internal iliac nodes. The prostatic urethra The prostatic urethra is the widest and most dilatable part of the entire male urethra. It is about 3 cm long and extends through the prostate gland from base to apex. The prostatic urethra is divided into proximal and distal segments of approximately equal length by an abrupt anterior angulation of its posterior wall at the midpoint between prostate apex and bladder neck.1 The angle of deviation is approximately 35 degrees, but can be quite variable and tends to be greater in men with nodular
Figure 1.1 (a) Schematic diagram of a midline section through the male lower urinary tract. The lumen of the bladder and of the urethra is dilated and the right half of the trigone (T) is shown as a surface feature. The detrusor muscle (D) is in direct continuity with the deep trigone (DT). The superficial trigone (ST) extends inferiorly as far as the verumontanum. IS, internal sphincter. The external striated urethral sphincter (ES) surrounds the membranous urethra. (b) Viewed from in front the trigone (T) is represented as a surface feature on the luminal aspect of the trigonal detrusor thickening. D, detrusor muscle; IS, internal sphincter; PS, periurethral striated muscle; ES, distal or external striated urethral sphincter.
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Page 4 hyperplasia.2 The prostatic urethra lies nearer the anterior than the posterior surface of the prostate. It is widest in the middle and narrowest below, adjoining the membranous part. In cross-section it appears crescent shaped in outline with the convex side facing ventrally (Fig. 1.2). The characteristic crescent shape is due to the presence on the posterior wall of a narrow median longitudinal ridge formed by an elevation of the mucous membrane and its subjacent tissue, called the urethral crest. On each side of the crest lies a shallow depression termed the prostatic sinus, the floor of which is pierced by the openings of the prostatic ducts. About the middle of the length of the urethral crest, the colliculus seminalis (or verumontanum) forms an elevation on which the slit-like orifice of the prostatic utricle is situated. On each side of, or just within, this orifice are the openings of two ejaculatory ducts. The prostatic utricle is a blind-ending diverticulum about 6 mm long which extends upwards and backwards within the substance of the prostate. It develops from the paramesonephric ducts or urogenital sinus and, as a consequence, is a remnant of the system which forms the reproductive tract in the female. The preprostatic urethra is a short segment lying between the bladder neck and base of the gland and is surrounded by a sleeve of smooth muscle fibers, forming the preprostatic sphincter. Tiny ducts and abortive acinar systems are scattered along the length of the proximal urethral segment and arborize exclusively inside the confines of the preprostatic sphincter forming the periurethral gland region. The preprostatic sphincter is thought to function during ejaculation to prevent retrograde flow of seminal fluid from the distal urethral segment. It may also
Figure 1.2 A horizontal section through the human prostate gland. The prostatic urethra appears crescent shaped in outline. (H & E) have resting tone which maintains closure of the preprostatic urethra, thereby aiding urinary continence. The preprostatic sphincter is compact on the posterior aspect of the urethra, but anteriorly its fibers do not form complete rings but terminate within the tissue of the anterior fibromuscular stroma. Slender bundles of smooth muscle cells also occur in the proximal part of the urethral crest, extending as far as the prostatic utricle where they become continuous with the muscle coat of the ejaculatory ducts. Proximally, these muscle bundles are continuous with those extending from the superficial trigone along the posterior wall of the preprostatic urethra. Below the openings of the ejaculatory ducts the distal prostatic urethra possesses a thin coat of smooth muscle, consisting of both circularly and longitudinally orientated muscle bundles which are themselves continuous with the strands of smooth muscle pervading the prostate gland. The distal urethral segment is also surrounded by a sphincter formed of small-diameter (15–20 μ m), striated muscle fibers separated by connective tissue (Fig. 1.3), which represent a proximal extension of the external urethral sphincter (rhabdosphincter) located distal to the prostate apex. The sphincter within the prostate gland is incomplete posterolaterally where the semi-circular fibers anchor into the prostatic stroma. Histochemical studies3,4 have shown that the small-diameter striated muscle fibers are almost all of the slowtwitch type and that similar fibers lie on the inner aspect of the external urethral sphincter surrounding the membranous urethra. These fibers are believed to be important in the maintenance of urinary continence. The small-diameter fibers merge peripherally with larger-diameter
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Figure 1.3 Small-diameter striated muscle fibers, separated by connective tissue, surround the distal prostatic urethra. (Masson’s trichrome stain.)
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Page 5 fibers, two-thirds of which are of the slow-twitch type and one-third of the fast-twitch type. These larger-diameter fibers may be a proximal extension of the striated muscle surrounding the bulb of the penis and help to empty the urethra during ejaculation and at the end of micturition. Histologic structure of the prostate In 1912 Lowsley5 presented a detailed description of the anatomy of the human prostate gland, based on embryonic and fetal studies. However, his scheme of median and lateral prostatic lobes was found to be inadequate as a model for the anatomy of the adult human prostate. This early concept of prostatic structure was modified by the work of Franks6 and by the more recent studies of McNeal2,7–9 and Tissell and Salander.10,11 Although these latter authors used entirely different examination techniques, the results of their studies generally seem to coincide with those of McNeal. McNeal studied prostates obtained at autopsy from adults and infants and from which numerous sections were taken in different planes. From his observations McNeal has described four distinct regions, each of which arises from a different segment of the prostatic urethra (Fig. 1.4). The largest part is the anterior or ventral fibromuscular and nonglandular region, which forms the ventral surface of the gland and which constitutes about one-third of the entire prostate.
Figure 1.4 Diagram of a sagittal section of prostate to show anatomic subdivisions (redrawn from McNeal2). CZ, central zone; PZ, peripheral zone; TZ, transitional zone; V, verumontanum; FS, fibromuscular stroma; D, detrusor; P, preprostatic sphincter; ES, external sphincter; ST, superficial trigone; BL, bladder lumen; U, urethral lumen. The glandular prostate can then be subdivided into three zones, as follows: • A peripheral zone, representing about 70% of the glandular part of the prostate. This zone forms the lateral and posterior or dorsal part of the organ. It may be regarded as a funnel that distally constitutes the apex of the prostate and cranially opens to receive the distal part of the wedge-shaped central zone. The ducts of the peripheral zone open into the distal prostatic urethra. They extend mainly laterally in the coronal plane, with major branches that curve anteriorly and minor branches that curve posteriorly. • A central zone, comprising about 25% of the glandular prostate. This zone is wedge-shaped and surrounds the ejaculatory ducts with its apex at the verumontanum and its base against the bladder neck. Thus the central zone is, at least in its distal part, surrounded by the peripheral zone and its ducts open into the prostatic urethra, in close proximity to the ejaculatory ducts. The central zone, like the peripheral zone, has a funnel shape to accommodate the proximal segment of the urethra. Both funnels are incomplete ventrally, where their borders are held together by the fibromuscular stroma. • The smallest glandular part comprises only about 5–10% of the prostate and has been called a transitional zone. This zone consists of two independent small lobes whose ducts leave the posterolateral recesses of the urethral wall at a single point, just proximal to the point of urethral angulation and at the lower border of the preprostatic sphincter. The main ducts of the transitional zone extend laterally around the distal border of the sphincter and curve sharply anteriorly, arborizing towards the bladder neck immediately external to the preprostatic sphincter and fanning out laterally. The most medial ducts and acini of the transitional zone curve medially to penetrate into the sphincter. McNeal’s concept of prostate anatomy was later confirmed by Blacklock and Bouskill,12 although the presence of a transitional zone could not be confirmed by other workers.13 McNeal described distinct histologic differences between the central and peripheral glandular zones which might indicate a difference in their functions.8 In the peripheral zone and transitional zone, ducts file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_5.html[09.07.2009 11:51:18]
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and acini are usually 0.15 and 0.3 mm in diameter and have simple rounded contours that are not perfectly circular because of prominent undulations of the epithelial border. The
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Page 6 undulations reflect the presence of corrugations of the wall, which presumably provide for expansion of the lumina as secretory reservoirs. Central zone ducts and acini are distinctively larger than those of the peripheral zone and transitional zone—up to 0.6 mm in diameter or larger. They become progressively larger and more elaborate as the duct territories expand toward the prostate base. Acini are clustered into lobules around a central subsidiary duct while both ducts and acini are polygonal in contour. The corrugations within the walls are very prominent and frequently form into intraluminal ridges that partially subdivide acini. Glandular lobes in the central zone are separated by bundles of compact smooth muscle cells, but the ratio of epithelium to stroma is higher than in the peripheral and transitional zones. The more abundant peripheral zone stroma is loosely woven with randomly arranged smooth muscle bundles (Fig. 1.5). There is an abrupt contrast in stromal morphology which delineates the boundary between central zone and peripheral zone. However, the contrast between the peripheral and transitional zones is less obvious or consistent. The stroma of the transitional zone is composed of interlacing bundles of compact smooth muscle cells that blend with the adjacent stroma of the preprostatic sphincter and anterior fibromuscular stroma. According to McNeal,14 stromal distinctions are less evident in older prostates and may be obliterated by disease. Tissel and Salander,10,11using a microdissection technique, were able to distinguish two dorsal, two lateral, and two median lobes of the human prostate. The lobes are arranged in an onion pattern, with the median lobes lying centrally around the ejaculatory ducts and the lateral and
Figure 1.5 Irregularly shaped prostatic acini from the peripheral zone. Randomly arranged smooth muscle bundles lie in the prostatic stroma. (H & E) dorsal lobes forming the outer layers. Each of these three pairs of lobes was found to have its own histologic characteristics,15 which were subsequently confirmed by others.16 Compared with the histologic pattern of McNeal’s central and peripheral zones,7 the description of the histology of the medial lobe given by Salander et al.15 has obvious similarities with the central zone. Similarly, the dorsal-lateral lobes correspond to the peripheral zone. Thus the two descriptions by and large coincide, especially as McNeal has acknowledged that the peripheral zone might be subdivided into two zones. The establishment of distinct anatomic and histologic lobes or zones in the human prostate has led to studies of the relationship between prostatic disease and different parts of the gland, and also the hormonal dependence of individual lobes and zones. Benign prostatic hyperplasia largely arises in the preprostatic glandular tissue and the preprostatic urethra, and McNeal often found small nodules in this part of the organ. Furthermore, in almost half of the prostates studied by McNeal, small carcinomas, less than 0.1 cm3 in volume, were detected, most of which originated in the peripheral zone and only a few in the central zone. Inflammatory changes were also most often seen in the peripheral zone. The epithelium of the glandular prostate Within each zone of the prostate, the entire duct-acinar system, with the exception of the main ducts near the urethra, is lined by columnar secretory cells whose appearance is identical between ducts and acini. The secretory cells are separated from the basement membrane and prostatic stroma by a layer of basal cells. These cells are generally flattened and lie parallel to the basement membrane, with small dark-staining nuclei and little cytoplasm. These basal cells are often quite inconspicuous and may appear to be absent from some of the ducts and acini. They are considered to form the proliferative compartment of the prostate epithelium and divide to give rise to mature secretory cells.17
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Compared with other regions of the prostate, the secretory cells of the central zone have a darker, more prominently granular cytoplasm and each cell possesses a relatively large nucleus. The luminal epithelial border tends to be uneven with individual cells protruding into the lumen. The secretory cells of the peripheral zone, the transitional zone, and the periurethral glands have smaller nuclei, uniformly situated towards the base. The cytoplasm is pale-staining and the cells present a relatively smooth luminal border.14
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Page 7 In all zones of the prostate, the epithelium contains a small population of randomly scattered endocrineparacrine cells,18–20 that are rich in serotonin-containing granules and contain neuron-specific enolase.19 Subpopulations of these cells also contain a variety of peptide hormones such as somatostatin,20 calcitonin,21 and bombesin.21 These cells normally occur in the basal cell layer and often possess laterally spreading dendritic processes (Fig. 1.6). However, they do not often appear to extend as far as the luminal surface. Their precise function remains unknown, although they are assumed to have a paracrine function, possibly in response to neural stimulation, thereby regulating the secretory processes of the mature gland. They may also have a significant role to play during prostatic growth and differentiation. Spherical bodies called prostatic concretions (or corpora amylacea) normally occur in some of the prostatic acini. They vary greatly in size and may become calcified and exceed 1 mm in diameter. In sections they appear as concentric lamellated bodies which are believed to be condensations of prostatic secretory products. The transitional epithelium, which lines the prostatic urethra and extends for a variable distance into the main prostatic ducts, differs histologically from that which lines the urinary bladder and also differs from the lining of the female urethra. The transitional epithelial cells of the prostatic urethra and main ducts have relatively sparse cytoplasm with no evidence of maturation into luminal umbrella cells. Instead, the luminal surface is lined by a single layer of columnar secretory cells that appear identical to the secretory epithelium of the peripheral zone.
Figure 1.6 Endocrine-paracrine cells with dendritic processes frequently occur in human prostatic epithelium (bombesin immunocyto-chemistry). Innervation of the prostate gland The human prostate gland receives a dual autonomic innervation from both parasympathetic (cholinergic) and sympathetic (noradrenergic) nerves13,22–26 via the prostatic nerve plexus, i.e. that part of the pelvic autonomic plexus that lies adjacent to the prostate gland. The pelvic plexus (and hence the prostatic plexus) receives parasympathetic input from the sacral segments of the spinal cord (S2–S4) and sympathetic fibers from the hypogastric (presacral) nerves (T10–L2).27 These nerves ramify within the prostatic plexus which contains both cholinergic and noradrenergic nerve cell bodies. The autonomic nerves which supply the prostate (and also the seminal vesicles, urethra, and corpora cavernosae) arise from the pelvic plexus and travel together with the vascular supply. These neurovascular bundles approach the base of the prostate on its posterior aspect and generally lie in the same coronal plane as its rectal surface.28 Most of the nerve branches to the prostate leave the neurovascular bundles at a level just above the prostate base and extend medially within a layer of fatty tissue. The nerve branches in these superior pedicles fan out over the prostatic capsule, which contains many autonomic ganglia embedded in a layer of fat. Some nerve branches continue medially over the prostate base to supply the central zone, while others fan out distally and penetrate the capsule at a very oblique angle. A few nerve branches leave the neurovascular bundles at the apex of the prostate via two small inferior pedicles and penetrate the capsule directly. The neurovascular bundles continue over the anterolateral aspect of the prostate to innervate the erectile tissue of the penis (and possibly the external urethral sphincter). Within the prostatic parenchyma small nerve branches lie immediately adjacent to the walls of the ducts and acini, while other nerves form branching plexuses among the smooth muscle bundles of the stroma. file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_7.html[09.07.2009 11:51:19]
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According to Gosling,25 both cholinergic (Fig. 1.7) and noradrenergic nerves (Fig. 1.8) innervate the smooth muscle bundles of the prostatic stroma, while cholinergic nerves also innervate the smooth muscle of the capsule. It is well known that under sympathetic stimulation (such as occurs during ejaculation) prostatic fluid is expelled into the urethra.29 The importance of sympathetic nerves in the motor control of prostatic musculature has been demonstrated by in vivo,30,31 in vitro and clinical studies,32–34 and forms the basis of the therapeutic use of α-blockade in the medical management of benign prostatic hypertrophy. Although initial studies (in vitro) of prostatic capsule showed it to have a cholinergic component with an atropine-sensitive contractile response to nerve
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Figure 1.7 Acetylcholinesterase-positive nerve fibers lie at the base of the prostatic acini and also occur in association with the smooth muscle bundles of the prostatic stroma. Human prostate gland.
Figure 1.8 Formaldehyde-induced fluorescence preparation showing a profusion of branching noradrenergic nerves in association with smooth muscle bundles in the human prostate gland. The orange colored granules within the prostatic epithelial cells are autofluorescent lysosomes. stimulation,32 subsequent reports have failed to provide evidence that muscarinic cholinoceptor stimulation plays a significant motor role within the prostate.35,36 A decrease in the density of adrenergic and acetylcholinesterase-positive nerves has been reported in hyperplastic tissue in man.37 The human prostate gland is also supplied by nerves containing a variety of neuropeptides,13,38–41 such as vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY) (Fig. 1.9), substance P (SP), calcitonin gene-related peptide (CGRP), somatostatin (SOM), and med- and eu-enkephalin (m-ENK and 1-ENK). As in other organs, it seems likely that at least some of these peptides coexist within the classical cholinergic and noradrenergic nerve fibers and serve as neuromodulators, neurotransmitters, or trophic factors. Both VIP and NPY are known to have
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Figure 1.9 Numerous neuropeptide Y (NPY)-immunoreactive nerve fibers lie at the base of these prostatic acini. Human prostate gland. motor functions elsewhere in the lower urinary and intestinal tracts. In the human urinary bladder, VIP produces a dose-related prolonged relaxation effect and is also a powerful vasodilator, whereas NPY is known as a pre- and postsynaptic modulator of adrenergic transmission. However, NPY is not only present in sympathetic nerves but can also occur in nonnoradrenergic nerves. Somatostatin, 1-ENK, and m-ENK have all been demonstrated in different minor populations of sympathetic nerves. In contrast, CGRP and SP are principally colocalized in sensory nerve fibers. SP is also known to produce contraction of detrusor and intestinal smooth muscle. CGRP is a potent inhibitor of SP degradation and also a potent vasodilator. It seems likely that SP and CGRP fulfill a primarily sensory neurotransmitter role within the prostate during ‘axon reflex’ activity.37 The presence of intrinsic autonomic ganglion cells has also been reported in the human prostate41 with a widespread distribution, occurring not only in the capsule but throughout the substance of the gland (Fig. 1.10). These ganglia contain both presumptive noradrenergic and cholinergic nerve cell bodies and, by analogy with intrinsic ganglia in other organs, it is likely that these nerve cells play an integrative and/or modulatory role in prostatic activity rather than acting as simple relay stations.41 Recently, nitric oxide (NO) has been implicated in the functional control of the human prostate, based on the immunohistochemical demonstration of nitric oxide synthase (NOS)-containing nerve fibers and ganglion cells within the prostatic stroma.42 These data have been interpreted as indicating that NO, serving as a neurotransmitter and as a paracrine factor, may modulate smooth muscle tone in the human prostate gland.
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Figure 1.10 An autonomic ganglion from the prostatic capsule containing both small DBHpositive (presumptive noradrenergic) and larger DBH-negative (presumptive cholinergic) nerve cell bodies. Human prostate gland. Neural control of prostatic secretion Numerous acetylcholinesterase-positive nerves lie at the base of the glandular acini of the prostate, forming a presumptive cholinergic secretomotor innervation,13,41 and it is well known that parasympathetic stimulation increases the rate of prostatic secretion.35 Immunohistochemical studies have shown that the subepithelial nerve fibers in the human prostate gland are rich in VIP,13,41,43 and thus VIP is considered to play a vital role in the regulation of secretory activity within the organ. VIP may also have an effect in the regulation of blood flow within the prostate, an increase in blood flow enhancing the secretory activity of the gland.43 Recently, NOS has been demonstrated in nerve fibers surrounding glandular acini in the human prostate gland, indicating the probable involvement of NO in the control of prostatic secretion.42,44The apparent co-localization of both VIP and NOS in the same subepithelial nerve fibers is highly suggestive of a cofunctional role for NO and VIP in the regulation of prostatic secretory activity.44 References 1. Glenister T W. The development of the utricle and of the so-called ‘middle’ or ‘median’ lobe of the human prostate. J Anat 1962; 96:443–455 2. McNeal J E. The prostate and prostatic urethra: a morphologic synthesis. J Urol 1972; 107:1008–1016 3. Elbadawi A, Mathews R, Light J K, Wheeler T M. Immunohistochemical and ultrastructural study of rhabdosphincter component of the prostatic capsule. J Urol 1997; 158:1819–1828 4. Ho K M T, McMurray G, Brading A F et al. Nitric oxide synthase in the heterogenous population of intramural striated muscle fibres of the human membranous urethral sphincter. J Urol 1998; 159:1091– 1096 5. Lowsley O S. The development of the human prostate gland with reference to the development of other structures at the neck of the urinary bladder. Am J Anat 1912; 13:299–349 6. Franks L M. Benign nodular hyperplasia of the prostate. A review. Ann R Coll Surg 1954; 14:92–106 7. McNeal J E. Regional morphology and pathology of the prostate. Am J Clin Pathol 1968; 49:347–357 8. McNeal J E. Origin and evolution of benign prostatic enlargement. Invest Urol 1978; 15:340–345 9. McNeal J E. Anatomy of the prostate: an historical survey of divergent views. Prostate 1980; 1:3–13 10. Tissell L E, Salander H. The lobes of the human prostate. Scand J Nephrol 1975; 9:185–191 11. Tissell L E, Salander H. Anatomy of the human prostate and its three paired lobes. In: Kimball F A, Buhl A E, Carter D B (eds). New approaches to the study of benign prostatic hyperplasia. New York: Alan R.Liss, 1984: 55–65 12. Blacklock N J, Bouskill K. The zonal anatomy of the prostate in man and in the rhesus monkey. Urol Res 1977; 5:163–167 13. Higgins J R A, Gosling J A. Studies on the structure and intrinsic innervation of the normal human prostate. Prostate 1989; Suppl 2:5–16 14. McNeal J E. Prostate. In: Sternberg S S (ed). Histology for pathologists. New York: Raven Press, 1992:749–763 15. Salander H, Johansson S, Tissel L G. The histology of the dorsal and medial prostatic lobes in man. Invest Urol 1981; 15:479–484 file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_9.html[09.07.2009 11:51:20]
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16. Stegmayr B, Busch C, Fritjofsson A, Ronquist G. Biochemical and morphologic studies of the prostate gland in men subjected to radical cystectomy. Ups J Med Sci 1985; 90:139–143 17. Dermer G B. Basal cell proliferation in benign prostatic hyperplasia. Cancer 1978; 41:1857–1862 18. Cohen R J, Glezerson G, Taylor L F et al. The neuroendocrine cell population of the human prostate gland. J Urol 1993; 150:365–368 19. Di Sant’ Agnese P A, de Mesy Jensen K L, Churukian J. Human prostate endocrine-paracrine (APUD) cells: distributional analysis with a comparison of serotonin and neuron-specific enolase immunoreactivity and silver stains. Arch Pathol Lab Med 1985; 109:607–612 20. Di Sant’ Agnese P A, de Mesy Jensen K L. Somatostatin and/or somatostatin like immunoreactive endocrine-
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Page 10 paracrine cells in the human prostate gland. Arch Pathol Lab Med 1984; 108:693–696 21. Di Sant’ Agnese P A. Calcitonin-like immunoreactive and bombesin-like immunoreactive endocrineparacrine cells of the human prostate. Arch Pathol Lab Med 1986; 110: 412–415 22. Baumgartner H G, Falck B, Holstein A F, Owman C H, Owman T. Adrenergic innervation of the human testis, epididymis, ductus deferens and prostate. A fluorescence microscopic and fluorimetric study. Z Zellforsch 1968; 90: 81–95 23. Gosling J A, Thompson S A. A neurohistochemical and histological study of peripheral autonomic neurons of the human bladder neck and prostate. Urol Int 1977; 32: 269–276 24. Vaalasti A, Hervonen A. Autonomic innervation of the human prostate. Invest Urol 1980; 17:293–297 25. Gosling J A. Autonomic innervation of the prostate. In: Hinman F (ed). Benign prostatic hypertrophy. New York: Springer-Verlag, 1983:349–360 26. Vaalasti A, Hervonen A. Nerve endings in the human prostate. Am J Anat 1980; 157:41–47 27. Langley J N, Anderson H K. The innervation of the pelvic and adjoining viscera. VI anatomical observations. J Physiol (Lond) 1896; 20:372–406 28. Lepor H, Gregerman M, Crosby R, Mostofi F K, Walsh P C. Precise localization of the autonomic nerves from the pelvic plexus to the corpora cavernosa: a detailed anatomical study of the adult male prostate. J Urol 1985; 133: 207–212 29. Brushini H, Schmidt R A, Tanagho E A. Neurologic control of prostatic secretion in the dog. Invest Urol 1978; 15: 288–291 30. Donker P J, Ivanovici F, Noach E L. Analyses of the urethral pressure profile by means of electromyography and the administration of drugs. Br J Urol 1972; 44:180 31. Furuya S, Kumamoto Y, Yokoyama E et al. Alpha-adrenergic activity and urethral pressure profilometry in prostatic zone in benign prostatic hypertrophy. J Urol 1982; 128: 836 32. Caine M, Raz S, Zeighler M. Adrenergic and cholinergic receptors in the human prostate, prostatic capsule and bladder neck. Br J Urol 1975; 47:193 33. Caine M. Clinical experience with α-adrenoceptor antagonists in benign prostatic hypertrophy. Fed Proc 1986; 45: 2604 34. Caine M. The present role of α-adrenoceptor blockers in the treatment of benign prostatic hypertrophy. J Urol 1986; 136:1 35. Smith E R, Lebeaux M T. The mediation of the canine prostatic secretion provoked by hypogastric nerve stimulation. Invest Urol 1970; 7:313–318 36. Hedlund H, Anderson K E, Larsson B. Alpha-adrenoceptors and muscarinic receptors in the isolated human prostate. J Urol 1985; 134:1291 37. Chapple C R, Crowe R, Gilpin S A et al. The innervation of the human prostate gland—the changes associated with benign enlargement. J Urol 1991; 146:1637–1644 38. Vaalasti A, Linnoila I, Hervonen A. Immunohistochemical demonstration of VIP, [Met5]- and [Leu5]enkephalin immunoreactive nerve fibres in the human prostate and seminal vesicles. Histochemistry 1980; 66: 89–98 39. Gu J, Polak J M, Probert L et al. Peptidergic innervation of the human male genital tract. J Urol 1983; 130:386–391 40. Adrian T E, Gu J, Allen J M et al. Neuropeptide Y in the human male genital tract. Life Sci 1984; 35:2643–2648 41. Crowe R, Chapple C R, Burnstock G. The human prostate gland: a histochemical and immunohistochemical study of neuropeptides, serotonin, dopamine-β-hydroxylase and acetylcholinesterase in autonomic nerves and ganglia. Br J Urol 1991; 68:53–61 42. Burnett A L, Maguire M P, Chamness S L et al. Characterization and localization of nitric oxide synthase in the human prostate. Urology 1995; 45:435–439 43. Tainio H. Peptidergic innervation of the human prostate, seminal vesicle and vas deferens. Acta Histochem 1995; 97:113–119 44. Block W, Klotz T, Loch C et al. Distribution of nitric oxide synthase implies a regulation of circulation, smooth muscle tone, and secretory function in the human prostate by nitric oxide. Prostate 1997; 33:1– 8
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Page 11 2 Embryology and development of the prostate E Shapiro M S Steiner Embryology of the prostate The terminal end of the hindgut is termed the ‘cloaca’, which is the Latin word for sewer. Septation of the cloaca by the urorectal septum begins at about 28 days of gestation.1 The rectum and primitive urogenital sinus (UGS) have formed by the 44th day of development. The primitive UGS proximal to the mesonephric duct develops into the vesicourethral canal, whereas the region distal of the mesonephric duct becomes the definitive UGS. The UGS adjacent to the bladder (pelvic urethra) is narrow and differentiates into the lower portion of the prostatic and membranous urethra.2 Embryologically, the cranial half of the pelvic urethra is derived from the endodermal UGS. Posteriorly, a component of mesonephric mesoderm originating from the bladder becomes incorporated into the pelvic urethra (superficial layer of the trigone). Later in development, this mesenchyme becomes smooth muscle that is continuous with the bladder (trigone). The caudal half of the pelvic urethra originates entirely from the UGS.3,4 At about the 10th week of gestation, the ductal network within the prostate develops from solid epithelial outgrowths, or prostatic buds. These prostatic buds evaginate from the endodermal UGS immediately below the bladder and penetrate into the Müllerian mesoderm which develops into the utricle and the mesonephric mesoderm, which develops into the ejaculatory ducts.5–9 The prostatic ducts rapidly lengthen, arborize, and canalize. By 13 weeks, 70 primary ducts are present and exhibit secretory cytodifferentiation.6,9 Prostate growth and development are dependent on androgen production by the fetal testes, which begins at about the eighth week of gestation.10–14 Unlike development of the Wolffian duct derivatives, which are dependent solely on testosterone, the differentiation of the UGS is dependent on the 5α-reduced form of testosterone, dihydrotestosterone (DHT). DHT is essential for the mediation of growth and development of the prostate from the pelvic portion of the UGS.12,15,16 Prostate morphology Much of our understanding of prostatic ductal development has been derived from the 1912 detailed anatomic descriptions of Lowsley.9 Lowsley serially sectioned the human fetal prostate and noted that, by 12 weeks, the branching ductal system consisted of five distinct groups. These lobes were termed the posterior, lateral (two), anterior, and middle lobes. The ducts of the posterior lobes originate from the floor of the prostatic urethra distal to the openings of the ejaculatory ducts and grow posteriorly. The epithelial buds of the two lateral lobes branch lateral to the verumontanum. The ducts of the middle lobe originate on the posterior urethra proximal to the openings to the ejaculatory ducts. The anterior lobe buds branch anterior to the verumontanum. The anterior lobe is prominent until the 16th week and then involutes to become an insignificant structure by 22 weeks. Although Lowsley’s work in the fetus was meticulous and precise, it does not explain the morphology of the adult prostate gland. The distinct boundaries between the five prostate lobes that Lowsley defined cannot be identified 2.5 months postnatally, nor do the five distinct lobes exist in the prepubertal and normal young adult prostate.5,17,18 Nonetheless, the terms posterior, lateral, middle, and anterior continue to be used to describe the lobes of the prostate, even though the middle and lateral lobes exist only in the aging male. Although Lowsley’s study emphasized the structural changes in the fetal prostate gland, Zondek and Zondek19 examined the continuous influence of maternal placental and fetal hormones on prostatic growth. The investigators noted periodic acid-Schiff (PAS)-positive staining in the prostate as early as 14 weeks of gestation, which correlates with secretion and growth activity in the fetus. The incidence and degree of PAS-positive reactions increase as fetal development progresses. Squamous metaplasia is found in the prostatic tubular epithelium at 22 weeks’ gestation and increases as the fetus matures. The squamous metaplasia resolves by acantholysis and exfoliation, resulting in the disappearance of most foci by birth. This process appears to depend upon a delicate balance of estrogen and testosterone. In congenital anomalies such as anencephaly, the fetus is exposed to excessive levels of circulating estrogen in the face of abnormally low testosterone production due to the absence of gonadotropin stimulation. The prostates of fetuses with this anomaly contain extensive squamous metaplasia and cyst formation.
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Page 12 Zondek and Zondek19 also examined tubular proliferation in the fetus. The fetal prostate is composed of only a few tubules widely separated by stroma. By 40 weeks, glandular epithelium proliferates and interspersed stromal elements decline. More recently Xia et al.20 qualitatively examined prostate growth, histogenesis, and secretory activity in 107 specimens from normal fetuses ranging in age from 20 weeks’ gestation to 1 month (postnatal). No sharply delineated ‘lobules’ were recognized. Two zones were identified, the inner submucosal zone (IZ) and the peripheral zone (PZ). The IZ was characterized by a concentric mass of fibromuscular connective tissue containing ducts at various stages of development. The PZ contained less concentrically organized fibromuscular connective tissue with secondary ducts, gland buds, and groups of acinar glands. The PZ was further divided into anterior, posterior, and two lateral regions. Three stages of development were also identified.20 During the bud stage (20–30 weeks), the buds at the ends of the ducts were simple, solid, and cellular and contained no lumen. Columnar cells were seen basally, and spindle-shaped cells were found near the bud center. The budtubule stage (31–36 weeks) was characterized by small collections of cellular buds and acini in both the PZ and IZ. In the acinotubular stage (37–42 weeks), distinct acinotubular gland clusters arise from the tubules with distinct lumina. Other investigators have noted that progression of ductal formation occurs, except in the periurethral zone. There, primitive rounded glands persist. Xia et al.20 also observed the presence of a glandular pattern in 25% of the fetal prostates, which resembled ‘budding’ atypical hyperplasia with ‘back-to-back’ glands, as described in the adult prostate. This pattern was seen as early as 24 weeks, but occurred more frequently in the 37- to 42-week gestational age glands. PAS staining intensity was directly related to gestational age, with the region of greatest staining activity in the lateral lobes of the PZ. Prostate-specific antigen (PSA) was identified in only 20% of the specimens, all of which were either older fetal or newborn glands. Squamous metaplasia was always found in association with the utricle and posterior wall of the urethra. Regions of involvement of the ducts with squamous metaplasia were variable. As the fetus progressed in gestational age, the areas of squamous metaplasia became less prominent. To date, this study is the most comprehensive examination of the embryologic development of the fetal prostate. Our understanding of prostate development has evolved from Lowsley and Venero’s concept of five lobes and the organized progression of ductal budding to zonal histogenesis (IZ and PZ). These studies focus primarily on the ductal development of the gland. Popek et al.21 examined development of the epithelium and also the qualitative morphologic changes that occur in the mesenchyme or stroma during development. They observed that the primitive mesenchyme is initially very loose, with the epithelium budding into the stroma. As the ductal network progresses, the loose peripheral primitive mesenchyme is replaced by concentrically organized smooth muscle bundles around acini. The stroma does not under-go a change to smooth muscle in the periurethral region. Two distinct smooth muscle bands are also noted; one is in association with the anterior fibromuscular stroma and one surrounds the utricle and ejaculatory ducts and is continuous with the smooth muscle of the seminal vesicles. Skeletal muscle is also seen peripherally in association with the prostatic capsule. Muscle-specific actin staining was noted as early as week 16, but mesenchymal expression was more notable by week 22. Prostate-specific acid phosphatase staining was seen in the larger ducts and cannulated acini by 17 weeks. PSA was generally absent in ductal and acinar cellular cytoplasm but was detected in areas of squamous metaplasia by 32 weeks. Shapiro et al.22 reported the application of computer image analysis that adapts Weibel’s multipurpose test grid and line intersect stereologic analysis to quantify the relative amounts of stroma and epithelium in prostate tissue. The original gray-density computer image analysis discriminated between the epithelial and stromal elements of prostatic tissue sections stained with hematoxylin and eosin (H & E). Shapiro et al.23 recently developed a new technique for quantifying the cellular elements of the prostate. The technique involves double immunoenzymatic staining and computer assisted color image analysis. The epithelium and smooth muscle were labeled with rabbit anti-desmin and a mouse antihuman prostatic acid phosphatase (PSAP), respectively. A rabbit peroxidase-anti-peroxidase complex was linked to the rabbit anti-desmin by a secondary antibody to rabbit antibody. The peroxidaseantiperoxidase complex was stained brown using the chromogen DAB. A mouse alkaline phosphataseanti-alkaline phosphatase (APAAP) complex was linked to the mouse anti-PSAP by a secondary antibody to mouse antibody. The APAAP complex was labeled using the chromogen fast red. The epithelium, glandular lumen, smooth muscle, and connective tissue stained red, colorless, dark brown, and light brown, respectively, using the double immunoenzymatic staining technique. The thresholds for the computer assisted color image analysis were set to file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_12.html[09.07.2009 11:51:21]
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Page 13 discriminate between the different staining properties of the prostatic cellular elements. Literature examining the morphometry of the prepubertal prostate is scarce.24 The only comprehensive study of prostatic morphometry in the prepubertal male has recently been reported by Shapiro et al.25 Quantitative morphometric studies were performed on pediatric and other nonhyperplastic prostate specimens obtained from 45 males ranging in age from 2 days to 40 years. The entire group was stratified based upon age into categories reflecting the neonatal, childhood, peri-pubertal, adolescent, and young adult period. Double immunoenzymatic staining using anti-actin and anti-PSAP was used to label the tissue components.23 Color image analysis demonstrated age-related changes in the density of smooth muscle that appear to parallel serum testosterone levels that vary due to the postnatal testosterone surge (age 30–60 days) and the rise in testosterone at the onset of puberty.12–14 A progressive decrease in smooth muscle area density throughout childhood, prepuberty and puberty was observed (Fig. 2.1). The density of smooth muscle significantly increased following puberty and throughout adolescence and early adulthood. There was a concomitant increase in connective tissue from the neonatal period throughout childhood, prepuberty, and puberty and a decrease after puberty and throughout adolescence and early adulthood. Since the changes in smooth muscle and connective tissue were inversely related, the per cent contribution of the stromal compartment to the total gland remained constant. No significant changes were seen in the epithelium or glandular lumen during these periods. The stromal to epithelial ratio remains constant from birth to age 40 in nonhyperplastic glands and is similar to those in asymptomatic and symptomatic benign prostatic hyperplasia (BPH) tissues (Table 2.1). These morphometric observations suggest that BPH is not a unique stromal process.25 These studies demonstrate that the stromal compartment is a dynamic structure, and the relationship between changes in cellular content and hormone milieu may be important to our understanding of growth of the prostate from birth to age 40 and the subsequent development of BPH. In addition to these observed dynamic changes in morphometry, the early testosterone surge in the young infant may be a critically important ‘imprinting’ event that may have an impact on the gland’s propensity for future abnormal prostatic growth and disease. Hormonal imprinting has been studied in the rat.26 Naslund and Coffey27 showed that early hormonal surges are requisite for normal adult prostate growth in the rat and that an alteration in the normal endocrine events that occur shortly after birth can have significant and permanent effects on the androgen sensitivity and growth of the adult
Figure 2.1 Bar graph illustrating the smooth muscle (SM), connective tissue (CT), and their combined components or stromal compartment of the prostate gland in groups I–V (From Shapiro E, Perlman E, Hartanto V et al. Morphometric analysis of pediatric and nonhyperplastic prostate glands: evidence that BPH is not a unique stromal process. Prostate 1997; 33:180. Reprinted by permission of Wiley-Liss, Inc. a division of John Wiley and Sons, Inc.)
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Page 14 Table 2.1 Per cent area density of the histologic components of the prostate. (From Shapiro E, Perlman E, Hartanto V et al. Morphometric analysis of pediatric and non-hyperplastic prostate glands: evidence that BPH is not a unique stromal process. Prostate 1997; 33:179. Reprinted by permission of Wiley-Liss, Inc. a division of John Wiley and Sons, Inc.)
*p<0.05. SM, smooth muscle; CT, connective tissue; E, epithelium; L, glandular lumen. prostate. These hormonal surges are thought to affect prostatic growth by altering the properties of the prostatic stem cells. The absolute number of these stem cells is important because it ultimately determines the size of the gland. Therefore, hormonal events occurring before puberty can imprint or program the prostatic size, androgen sensitivity, and function and maintenance of the stem cells. In order to elucidate further the growth and development of the fetal prostate, Shapiro et al. (unpublished data) step-sectioned fetal prostates of 9.5–40 weeks’ gestation to determine the macroscopic growth rate and quantitative morphometry using color image analysis. Three-dimensional reconstruction of the fetal prostate gland has been performed to define the structural changes throughout the gland in the smooth muscle, connective tissue, and urethral lumen, as well as to define ductal budding and morphogenesis (Shapiro et al., unpublished data). Preliminary observations indicate that the mean cross-sectional area (csa) of the fetal prostate increases significantly in early gestation (Shapiro et al., unpublished data): at gestational age 9.5 weeks, 11.5 weeks, 13.0 weeks, and 16.5 weeks the csa is 0.42 mm2, 1.20 mm2, 1.96 mm2, and 4.95 mm2, respectively. The histologic composition of these prostates has been determined using double immunoenzymatic staining and color assisted computer image analysis.23 We have shown that the connective tissue comprises a significant component (approximately 65%) of the fetal gland (gestational age 9.5–16.5 weeks), while the smooth muscle component during these early weeks of prostatic development comprises only 25%. The epithelium and lumen together represent about 5–10% of the gland. Although the morphometry of the older fetus has yet to be determined, the stromal compartment of the neonate/infant gland (age 0–1 year) is known to be slightly smaller (80%), and is composed of almost 50% smooth muscle and 30% connective tissue. This again denotes dynamic changes in the stromal compartment during fetal development. Timms et al.28 investigated ductal budding and branching patterns in the developing prostate using threedimensional computer-assisted serial section reconstruction. He studied fetal mice and rats and also examined two human fetuses (crown-rump length 70 mm and 100 mm). Timms showed that ventral, lateral, and dorsal lines of epithelial buds follow a ventro-dorsal and cranial-caudal axis. His findings suggest that prostate ductal budding exhibits patterns compatible with the current concept of zonal anatomy.29–32 McNeal29–32 described the zonal anatomy of the prostate based on examination of the gland in different planes of section. The urethra divides the prostate into an anterior fibromuscular and posterior glandular portion and is the primary anatomic reference point. The urethra has a 35-degree angulation. The point of angulation divides the urethra into proximal and distal segments of about equal length (Fig. 2.2). Two principal regions of the glandular prostate are the PZ (approximately 75% of the total glandular volume) and the central zone (CZ) (approximately 25% of the total volume). The CZ and its ductal orifices are in close association with the ejaculatory ducts and their orifices near the verumontanum in the distal urethral segment, which extends from the prostatic apex to the verumontanum. The PZ ducts enter the urethra separately from those of the CZ and are in association primarily with the distal urethral segment. The CZ morphology is composed of ducts that branch into large, irregularly contoured acini, whereas the PZ ducts branch into small, round, regular acini.31–33 The epithelial cells in the CZ have granular cytoplasm and enlarged nuclei located at various levels from the basement membrane, whereas the epithelial cells of the PZ
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Page 15 have clear cytoplasm and small, dark nuclei located uniformly along the basal aspect of the basement membrane. The stroma of the CZ is long and compact and closely associated with the acini, whereas that of the PZ is random, with loose interconnections. These morphologic histologic differences between the PZ and CZ may be explained by the different embryonic origins. The ejaculatory ducts traverse the center of the CZ, and the epithelium of the CZ is similar to that of the seminal vesicle, suggesting a Wolffian duct origin. The PZ presumably is derived from the UGS. The transitional zone (TZ) accounts for less than 5–10% of the glandular volume and is closely related to the proximal urethral segment.31,32,34 The cylinder of the striated muscle surrounding the proximal urethral segment is termed the ‘preprostatic sphincter’, which prevents retrograde ejaculation. Lateral to this sphincter are two small lobes that are histologically similar to the PZ. The stroma of the TZ is dense and compact. The TZ is
Figure 2.2 Sagittal diagram of distal prostatic urethral segment (UD), proximal urethral segment (UP), and ejaculatory ducts (E) showing their relationships to a sagittal section of the anteromedial nonglandular tissues (bladder neck (bn), anterior fibromuscular stroma (fm), preprostatic sphincter (s), distal striated sphincter (s)). These structures are shown in relation to a three-dimensional representation of the glandular prostate (central zone (CZ), peripheral zone (PZ), transitional zone (TX)). Arrows indicate the coronal plane (C) along the distal urethral segment, which is the plane of greatest extent of glandular prostate, and the oblique coronal plane (OC) along the proximal urethral segment. (From McNeal J E. Normal histology of the prostate. Am J Surg Pathol 1988; 12:619, with permission.) adherent to the external aspect of the periprostatic sphincter, and its glands penetrate the sphincter, whereas the peripheral fibers of the sphincter penetrate the TZ stroma. The periurethral region of the prostate comprises less than 1% of the total glandular volume (Fig. 2.3).31,32 This region contains tiny ducts arising from the proximal urethral segment that are embedded in the periurethral smooth muscle. The periurethral glands are histologically similar to those of the PZ and TZ. This is not unexpected since the TZ and the periurethral gland region have a common embryonic urogenital sinus origin and are the sites of origin of BPH (Fig. 2.4). Hyperplastic nodules develop as early as the fourth decade. Periurethral nodules are stromal and resemble embryonic mesenchyme, where-as TZ nodules are glandular. Nodule genesis is focal and occurs randomly within areas of susceptibility. The initial abnormality in nodule genesis may be spontaneous reversion of a clone of stromal cells to the embryonic state. Growth potential can then be mediated through coordinated stromal-epithelial interactions. This postulation is supported by qualitative observations of ductal development that is tangential to nodule borders. These ducts may show epithelial hyperplasia and budding of new branches on only the duct wall facing the center of the nodule. These eccentric effects suggest that an induction or interaction is occurring on only one side of the duct.
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Figure 2.3 Oblique coronal plane of prostate subdivided by the preprostatic sphincter (S) into the transitional zone (T) and periurethral region (U). Main transitional zone ducts arise from the urethra at the base of the verumontanum (V) and pass around the distal border of the sphincter as they arborize toward the bladder. P, peripheral zone of glandular prostate. (From McNeal J E. Origin and evolution of benign prostatic enlargement. Invest Urol 1978; 15:340–343, with permission.)
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Figure 2.4 Prostate with few nodules superimposed on an oblique coronal diagram. Centers of glandular nodules are plotted and lie primarily within the transitional zone (T), especially near or within the sphincter (S). Stromal nodules are plotted on the right. They are fewer in number and are often periurethral (U) or in the medial sphincter. (b) Prostate with many nodules and diffusely enlarged transition zone. Glandular nodules (left) are generally located within the transitional zone. Stromal nodules (right) occur primarily in the periurethral region. (From McNeal J E. Origin and evolution of benign prostatic enlargement. Invest Urol 1978; 15:340–343, with permission.) The hallmark of embryonic development is the formation of new architecture. It seems logical that the development of BPH nodules, which is repressed until the fourth or fifth decade of life, may be a ‘reawakening of embryonic capabilities’ in the adult. Stromal-epithelial interactions in prostate development The formation of new ductal acinar architecture of BPH deviates from that in the normal development of most organs.31,35 First, the acinar development of the prostate should be completed during puberty. The prostate is the only organ that demonstrates new growth as part of the aging process. Also, the ductal system in BPH forms differently from that of the embryonic prostate. The ducts of the embryonic prostate branch parallel and away from each other rather than toward each other, as seen in BPH nodules. Although the specific biochemical factors initiating new growth of the prostate are unknown, there is increasing evidence that stromal cells are intimately involved.36–38 The inductive role of the stromal cells in the adult prostate resulting in new nodule formation, is, as mentioned above, thought of as (an embryonic reawakening’. These investigations by Cunha15,39–50 have examined the interaction between epithelium and mesenchyme, as well as the androgenic mediation of the events that result in prostatic growth and development. Stromal and epithelial interactions that occur in the developing prostate are androgen dependent.51 Chemical or surgical castration of the fetus during the critical periods of sexual development results in the inhibition of development of the prostate and other male accessory sex glands.52–60 During the postnatal period, androgen remains important for prostate growth, as castration at this time will inhibit growth and development.51,61,62 Although the fetal testis elaborates testosterone, it is DHT that is the active intracellular androgen responsible for prostatic morphogenesis. The enzyme 5αreductase has been localized in the UGS and external genitalia of humans.12,16,44,63,64 Inhibition of this enzyme in the male rat results in feminization of the external genitalia and urethra and the partial inhibition of prostatic development.65 Although DHT is important for prostatic growth, the developing prostate may be responsive to exceedingly low levels of DHT or other androgens.65 Also, some aspects of postnatal prostatic growth may be independent of androgens, as castration in the rat during this
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period does not completely inhibit prostate development.51,61,62 This suggests that other nonandrogen growth factors such as peptide growth factors are capable of mediating arborization and growth of prostatic ducts. The 5α-reductase deficiency syndrome is a form of autosomal recessive male pseudohermaphroditism characterized by severe penoscrotal hypospadias, a blind vaginal pouch, and normal testes with normal epididymes, vasa deferentia, and seminal vesicles.66,67 The ejaculatory ducts terminate in the blindending vagina, and the prostate is small or undetectable. The phenotypic appearance is female without breast development. The selective effects of testosterone and DHT are defined since the defect in virilization during embryogenesis is limited to the UGS and the anlage of the external genitalia. Testicular feminization syndrome (Tfm) results in complete failure of the prostate to develop.68 Androgen receptors are defective or absent. The Wolffian ducts undergo degeneration. The external genitalia are
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Page 17 feminized despite normal testosterone levels. Testicular feminization and 5α-reductase deficiency syndromes provide clinical models for understanding the profound effect of DHT on prostate morphogenesis. Analysis of tissue recombinant experiments utilizing Tfm mice has demonstrated the role of stromalepithelial interactions.69 These mice have defective androgen receptors and fail to develop prostates. When tissue recombinant constructed of wild-type mesenchyme and Tfm epithelium are exposed to physiologic androgen levels as a result of grafting of the recombinants into intact male hosts, normal prostatic morphogenesis ensues.42,48,70 When the Trm mesenchyme is used with either the Tfm or the wild-type epithelium, the prostate does not form. These studies suggest that the mesenchyme is the actual target which elaborates other local growth factors that mediate androgen effects on the epithelium. The importance of DHT in prostate development is further supported by the presence of DHT receptor binding sites in wildtype UGS,71–74 since these binding sites are absent in the Tfm urogenital mesenchyme.48 The rat and mouse models of prostate development47,75,76 have delineated the lobar and ductal development, hormonal receptor status, and sex steroid requirements for growth. In the rodent, prostatic morphogenesis continues from late fetal life until sexual maturity.47 In these rodent species, the prostatic ducts are organized and encapsulated into individual lobes which emerge centrally from the urethra and extend peripherally before branching. Microdissections of these glands have shown a compound ductal system lacking true acini.75 Each of the four paired lobes has a distinct ductal branching pattern. The ducts are lined with a pseudostratified columnar secreting epithelium and each duct is surrounded by a layer of smooth muscle.77–81 Along the basement membrane are nonsecretory basal epithelial cells which may function as reserve or stem cells capable of differentiation. The epithelial morphology varies along the proximal-distal axis of the ducts, accompanied by differences in the function of these cells. Plasma membrane proteins,47 secretory proteins,82 and proteins governing cell death and degeneration82–84 are differentially expressed in specific regions along the duct. The stroma in these rodent models consists of fibroblasts, smooth muscle cells, blood vessels, connective tissue, nerve terminals, and lymphatics with an extracellular matrix of collagen.85 The stroma is subdivided into periacinar and interacinar stroma.86 The periacinar stroma constitutes several layers of smooth muscle separated from the ductal epithelium by the basal lamina.78,87 Endocrinology of prostatic development Development of the prostate is androgen dependent11,12,14,36,47,88 and DHT is the active intracellular androgen. Castration of neonatal mice inhibits continued growth and development, while some aspects of neonatal growth may be androgen independent.47,62,89 In rodents, androgen receptors (ARs) are expressed prenatally in the mesenchyme but not in the epithelium.71–74 At the end of the first postnatal week, the epithelial ARs appear when duct canalization occurs.71 The timetable and distribution of AR expression have been further studied by Cooke et al.90 They showed that functional fetal mouse ARs (capable of ligand binding) are present on gestational days 13– 14 in the UGS and Wolffian duct mesenchyme, but not in the epithelium. At this early time, only AR mRNA is present in the epithelium. When functional epithelial ARs appear, they do so in a cranial-caudal direction in the Wolffian duct and UGS over the late fetal/early neonatal periods. Since differentiation, growth, and early morphogenesis of the UGS and Wolffian duct structures are androgen dependent, early androgen effects must be mediated through the ARs of the mesenchyme of these structures.90 Cunha’s tissue recombinant experiments47,48 demonstrate prostatic development when normal UGS mesenchyme (UGM) and Tfm UGS epithelium are grafted into a male host. A critical paracrine relationship exists between the mesenchyme and epithelium during androgen-dependent morphogenesis. Regional differences in androgen sensitivity have been demonstrated along the ductal axis.75,82,84 The proximal duct is relatively androgen independent, while the distal duct tips are highly androgen dependent. Prins et al.91 have shown no differences in functional AR levels and 5α-reductase levels along the ducts in the 15-, 30-, or 100-day-old-rat. Recent investigations by Prins and Birch,92 using antibodies to rat ARs have shown that in the rat the basal epithelium expresses ARs as early as day 1. These ARs may act as direct targets of androgen effects of the epithelium during prostate development, even though initial epithelial AR induction may be an androgen-dependent process mediated by AR+ mesenchyme during late fetal life. Luminal epithelium does not appear until day 5–10. When present, it stains intensely for ARs. Also, periductal mesenchyme shows differentiation into smooth muscle by day 3–5. These smooth muscle cells are also strongly AR+, while the interductal fibroblasts show fewer AR+ file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_17.html[09.07.2009 11:51:23]
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Page 18 cells. These smooth muscle cells may be important targets for androgen-mediated morphogenesis. Prins92,93 also examined the effects of neonatal estrogen exposure on the development of the ARs. Estrogen receptors (ERs) have been shown to be strongly expressed in the rat prostate94 and mouse prostate mesenchyme.95 While the stroma is strongly ER+, the prostate smooth muscle is weakly to negatively staining after differentiatThere are no ERs in the epithelium of the prostate. Brief ing from mesenchyme. Fibroblasts remain strongly ER+. exposure to neonatal estrogen will downregulate ARs and permanently alter their expression, as well as retard ductal development.92,93 Smooth muscle development is generally unaffected, as is the development of basal cells. Estrogenization does not inhibit epithelial cell differentiation (determined by the appearance of luminal cell cytokeratins) completely, indicating that initiation of cytodifferentiation precedes elevated AR expression rather than increasing AR triggering cytodifferentiation. These experiments suggest that functional differentiation is dependent on AR expression in epithelial cells. The ventral prostate epithelial cells express prostate binding protein only after cytodifferentiation of distal duct tips occurs where AR immunostaining was seen. These studies support previous observations by Donjacour and Cunha96 using tissue recombinant experiments. Although UGM from normal mice instructively induced prostate morphology in wild-type, as well as the Tfm urinary tract epithelium, tissue recombinants of UGM and Tfm bladder or urethral epithelium cannot produce complete prostate cytodifferentiation or secretory proteins. Epithelial ARs are, therefore, important to the final states of morphogenesis and the initiation of prostate secretory activity. Tissue recombinant experiments have also been used to examine epithelial-mesenchymal interactions on the differentiation and organization of prostatic smooth muscle.97 Experiments combined adult prostatic epithelium (PRE) with UGM or seminal vesicle mesenchyme (SVM) or bladder epithelium (BLE) with UGM or SVM. Prostatic ducts developed in all tissue recombinants when UGM was used with either epithelium. Smooth muscle cells also organized into sheets resembling prostate. When SVM was combined with either epithelium, the prostatic ducts were surrounded by thick smooth muscle cells resembling seminal vesicle. The smooth muscle was unorganized in grafts of SVM or UGM. These experiments suggest that male urogenital gland mesenchyme dictates spatial organization, but smooth muscle differentiation is induced by epithelium. Urothelium may also direct the organization of smooth muscle tissue, since urothelium is thought to be a potent inducer of smooth muscle differentiation. Cunha and Donjacour47 have shown that the proximal segments of prostatic ducts near the urethra express urothelial membrane antigen and have associated thick layers of smooth muscle cells surrounding them. Role of growth factors in prostatic development Peptide growth factors may be direct mediators of androgen action and responsible for mediating the epithelial-mesenchymal microenvironment through either autocrine or paracrine pathways.98–101 These growth factors are regulated by androgens, suggesting that androgens may only indirectly influence growth. Peptide growth factors are part of a large family of proliferating and differentiating regulatory factors and may be important in prostate growth. Almost a decade ago, Norman et al.102 combined mouse UGM with an adult prostate epithelial duct tip. The mesenchyme induced ductal proliferation and arborization of adult epithelium, which demonstrated that the adult prostate has the potential for new growth by ‘reawakening’ of early prostatic embryonic mesenchymal-epithelial interactions.28–32,47 These findings that adult prostate treated with androgens does not grow, but embryonic mesenchyme is effective in inducing growth of adult prostate, suggest that the mesenchyme may elaborate other local factors that stimulate adult prostatic growth. Peptide growth factors are those local factors most likely responsible for mediating mesenchymal and epithelial interactions important for prostate development, since: • Peptide growth factors are expressed in either mesenchymal or epithelial components of developing prostate.47,49,103 • Isolated prostatic, epithelial, and stromal cells respond to peptide growth factors in vitro.49,104 • Prostatic mesenchymal and epithelial cells express specific membrane receptors for peptide growth factors.105–107 • Neutralizing antibodies for a peptide growth factor or its receptor inhibit biological effects.108–111 • Overexpression of peptide growth factors in transgenic mice perturbs prostatic growth and development.112–114 • Androgens directly influence the expression of peptide growth factors by prostate cells.111,115,116
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Page 19 • Androgen production is modulated by peptide growth factors.117,118 Epidermal growth factor (EGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF), and transforming growth factor β (TGFβ) family members have been found in normal prostate.36,119–122 The interplay between the stimulatory growth factors (EGF, TGFα, IGF, and FGF) and inhibitory growth factors (TGFβ1–3) regulates the epithelial and mesenchymal interactions responsible for prostatic development.123 Although TGFα and EGF utilize the same EGF receptor to enhance prostate cell proliferation. TGFα is preferentially expressed during periods of prenatal and postnatal prostate epithelial development.124 TGFα appears to stimulate prostatic ductal proliferation during development since overproduction of TGFα in prostates from TGFα transgenic mice resulted in prostatic ductal hyperplasia.114 Interestingly, FGF family members are mitogenic for both prostatic epithelial and mesenchymal cells.108,125,126 Perhaps the strongest evidence for their role in the embryonic reawakening of mesenchymal and epithelial interactions leading to prostatic growth is based on transgenic mice that over produce int-2, which is FGF-like growth factor.112,113 These int-2 transgenic mice exhibit exuberant prostatic hyperplasia with prostates up to 20-fold larger than control animals. The prostatic hyperplasia was similar to human BPH.112,113 Another FGF family member, KGF, is unique as it is produced by stromal cells but stimulates only epithelial growth.127 Similarly, IGF appears to stimulate prostatic epithelial proliferation selectively.128 This suggests that peptide growth factors can specifically influence either epithelial or mesenchymal cells during prostatic development. TGFβ family members have multifunctional biological properties. TGFβ inhibits normal prostatic epithelial growth, but stimulates prostatic mesenchymal cells.123 Steiner (unpublished data) has performed preliminary studies focusing on defining the important factors on prostate development. He has utilized TGFβ1 transgenic mice which overexpress TGFβ1.129,130 Overexpression of TGFβ1 alters prostate development by decreasing prostate ductal branching and increasing smooth muscle surrounding the acinar ducts (Steiner, unpublished data).112–114 Moreover, the anterior prostate had evidence of only primary ductal branching—the involuted or ‘aborted’ ductal branching—as seen in the development of distal ductal tips in androgen-deprived animals (Steiner, unpublished data). The effects of androgens on growth factors have generally been investigated in adult rats when glandular growth is minimal.49 This is the case for studies with TGFβ, which have shown that, following castration, there is a cascade of events, one of which is a marked increase in the level of TGFβ1 mRNA expression and TGFβ1 receptor binding sites in the rat ventral prostate.111,116,131 TGFβ1 has also been shown to inhibit normal proliferation of prostatic epithelial cells in culture. Foster and Cunha101 have recently investigated the role of TGFβ1 during prostate development. Rat anterior prostate is grown in vitro in a serum-free culture. The newborn rat anterior prostate consists of mesenchyme and unbranched epithelial buds. When testosterone is added for 6 days, there is ductal branching and morphogenesis. The trophic effects of testosterone and DHT can be inhibited by adding TGFβ1 to the culture medium. This inhibition occurs in a dose-dependent fashion. Thus, TGFβ plays a role in limiting ductal proliferation and arborization as well as stimulating mesenchymal cell growth (smooth muscle). Peptide growth factors appear to be the direct mediators of androgen action. Following androgen withdrawal, the production of stimulatory peptide growth factors EGF, IGF, and FGF by prostate cells decreases, whereas there is an increase in the expression of the inhibitory peptide growth factor TGFβ1 and TGFβ1 receptors.115,120,132,133 The net effect of these peptide growth factor alterations is prostatic involution. Androgen replacement re-establishes normal EGF, IGF, and FGF levels and suppresses TGFβ1, and the prostate regrows towards its original size.123 Peptide growth factors may be the embryonic inducers that initiate adult prostate growth. FGF and TGFβ family members have been implicated in the development of BPH.123 Mori et al.134 have reported that basic FGF (bFGF) and TGFβ2 mRNA are elevated in human BPH. Moreover, extracts of human BPH contain bFGF-like activity that enhances growth of human prostate epithelial cells and prostate-derived fibroblasts in culture.108 TGFβ is known to stimulate production of bFGF mRNA and protein in prostatederived stromal cells.135 Thus, a stromal BPH nodule may be formed when bFGF and TGFβ2 both stimulate stromal proliferation. The degree of interplay between TGFβ2 and bFGF will have differential effects on prostatic epithelial-stromal interactions, resulting in varying amounts of stromal and glandular hyperplasia.
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Page 20 Evidence that peptide growth factors contribute to human fetal prostate development Although the precise cellular and molecular mechanisms remain unclear, androgens and peptide growth factors appear to mediate the mesenchymal and epithelial interactions needed for normal prostate morphogenesis. The stroma of the developing prostate, which is thought to be the target of androgen stimulation, elaborates factors that induce glandular proliferation.39 The androgen receptor is expressed prenatally in the mouse prostatic mesenchyme, but not in the epithelium.136 Based on these observations, Tenniswood137 proposed that paracrine interactions between the androgen-receptorpositive mesenchyme and the androgen-receptor-negative epithelium may be mediated by a stromaderived growth factor capable of regulating epithelial cell proliferation. Prostate organ culture studies provide direct evidence for such interactions between stroma and epithelium; DHT promotes mitogenesis of stromal cells and stromal cells secrete fibroblast-derived soluble growth factors which stimulate epithelial proliferation.138 Peptide growth factors appear to be those soluble factors that mediate androgen effects on postnatal prostatic growth, but their role in prenatal prostate development is unknown. Nonetheless, experimental evidence examining the interactions of peptide growth factor members of the EGF and TGFβ families and androgens in prostate tissue has provided some mechanistic clues.139 Since EGF is under androgen control,132 and is required for epithelial cell proliferation in vitro, it may be one of the stroma-derived growth factors (SDGF).133 However, it is not known whether EGF is synthesized by the prostatic epithelial or stromal cells. Peptide growth factors have been shown to be regulated by androgens, suggesting that androgens may only indirectly influence prostate growth. One member of the EGF family, TGFα, is preferentially expressed during periods of pre- and postnatal prostate epithelial development.124 TGFβ is a multifunctional family, which generally inhibits growth of many types of epithelial cells and stimulates most mesenchymal cells.123 In transgenic mice, overexpression of TGFβ1 appears to alter prostate development by decreasing ductal branching and increasing smooth muscle surrounding the acinar ducts.113 Studies in rats have shown that castration is followed by a cascade of events including a downregulation of TGFα and a marked increase in TGFβ1 mRNA expression and TGFβ1 receptor binding sites in ventral prostate.111,116,131Finally, emerging studies have confirmed that some aspects of postnatal prostatic growth are androgen independent, as castration does not completely inhibit prostate development, supporting a role for peptide growth factors.51,62 Indirect evidence suggests that it is the interplay between stimulatory growth factors (TGFα) and inhibitory growth factors (TGFβ1–3) that regulates in part the mesenchymal and epithelial interactions responsible for prostate development. The exact interrelationship between androgens and peptide growth factors remains to be elucidated. Raghow et al.140 have performed studies that support the hypothesis that peptide growth factors may be the mediators of androgenic action in mesenchymal and epithelial interactions responsible for the early prostate development. Prostatic development is dependent not only on the presence of testosterone, but also on its conversion to DHT. Although testosterone production and Leydig cell hyperplasia begin at the eighth week of gestation,10,11 serum testosterone concentrations peak at about 13–16 weeks of gestational age, and gradually they decline to female testosterone levels.141 In vitro experimental evidence suggests that androgens may play only a permissive role, whereas peptide growth factors may be the direct mediators of androgen action. Prostate cell proliferation in vitro is dependent on EGF or βFGF, but not androgens.133 DHT has been shown to modulate the expression of TGFα, EGF, βFGF, and TGFβ in prostate.123 Organ culture studies have revealed that TGFβ1 can inhibit prostate ductal proliferation and branching morphogenesis. Moreover, βFGF can induce ductal proliferation independent of androgens.142 Hence, fetal prostate development may only be indirectly dependent on androgens, and peptide growth factors may be the direct mediators of androgen action. The expression of the enzyme 5α-reductase during the early phase (11–16.5 weeks) of fetal prostate development is confined to the prostatic mesenchyme and urothelium, with no detectable staining in the fetal prostatic epithelial cells.143 This pattern of expression is similar to human and rat male external genitalia and prostate differentiation, which is dependent upon local DHT formation early in gestation.66,67,144 In the adult rat prostate, George et al.145 have stated that 5α-reductase gene expression is under feed-forward control, in which product of the enzyme, DHT, stimulates the expression of the gene. However, no such feed-forward regulation of this enzyme was detected in the fetal rat prostate.146 Inhibition of the 5α-reductase enzyme in the male rat results in feminization of the external genitalia and urethra and partial inhibition of prostatic development. As previously discussed, in man, the 5α-reductase deficiency syndrome is recognized as male pseudohermaphroditism characterized by a small or file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_20.html[09.07.2009 11:51:25]
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Page 21 undetectable prostate.65,66 Consequently, 5α-reductase and DHT are critical for normal human prostate development.147 In humans, androgen receptor was initially present in the mesenchyme and urothelium, but with the fetal androgen surge, the prostatic epithelium had greater AR staining.143 This suggests that DHT is produced by the AR+ mesenchyme and affects the AR+ epithelial cells by paracrine signaling pathways. Similarly, in rodent prostate development, androgen receptors are expressed prenatally in the mesenchyme, but not in the epithelium.71–73 If the corresponding urogenital mesenchyme lacks AR, as in the testicular feminization (Tfm) syndrome, the prostate does not develop, whereas AR+ urogenital sinus mesenchyme was able to induce AR− Tfm epithelium to develop into epithelium.47 Hence, tissue recombinant experiments46,47 have demonstrated the critical paracrine relationship between the mesenchyme and epithelium during androgen-dependent morphogenesis. Donjacour and Cunha,51 in similar mouse tissue recombinant experiments, showed the importance of epithelial ARs to both prostate development and cytodifferentiation to secretory epithelium. Thus, the presence of ARs and DHT is necessary to stimulate mesenchymal elaboration of stromal factors. Raghow et al. have shown that some of those elaborated factors are members of the EGF and TGFβ families. TGFα, TGFβ1, and TGFβ3 were present in the mesenchyme at significant levels during the period of prostate development prior to the androgen surge (9.5–11.5 weeks).140 In contrast, TGFβ2 increased measurably only after 13 weeks, simultaneous with the peak of androgen production by the testes. These results suggest androgens modulate the differential expression of peptide growth factors during fetal prostate development.140 Furthermore, the presence of DHT with the appearance of 5α-reductase and AR+ epithelium was associated with the greatest intensity of immunostaining for TGFα and TGFβ3 in the epithelium during weeks 13–16.5 of gestation.140 Although TGFα, TGFβ1, and TGFβ3 were present initially in the mesenchyme, they later appeared in the epithelium during the androgen surge.140 Hence, it appears that initially DHT only indirectly influences prostatic epithelium by directly inducing the elaboration of mesenchymal factors that diffuse to affect the epithelium in a paracrine fashion. This is consistent with other investigators who have shown in developing rat prostate that the urogenital mesenchyme (UGM) induces epithelial ductal morphogenesis and epithelial androgen receptors, regulates epithelial proliferation, and specifies the expression of prostate-specific secretory proteins.45,148–151 The level of TGFβ1 was initially high during the early weeks of fetal prostate development, but then declined during the period of androgen surge, to the baseline low levels later at about 20 weeks.140 This reciprocal relationship between presence of DHT and TGFβ1 level seems to suggest downregulation of TGFβ1 by androgens during the period of active fetal prostate development. The downregulation of mesenchymal TGFβ1 by DHT following the androgen surge may be one of the ways mesenchyme induces epithelial differentiation during fetal prostate development. TGFβ is primarily a growth inhibitor and antagonizes other stimulatory growth factors; however, not much is known about the differential roles of the specific TGFβ isoforms. Raghow et al.140 have shown higher levels of TGFα and TGFβ3 in the prostatic epithelium during the period of androgen surge, suggesting DHT regulation of this TGFβ isoform in a manner similar to that of mitogenic growth factor TGFβ. TGFα was initially thought to be produced exclusively by transformed cells, but is now known to be present in rapidly growing normal tissues.152–156 Overexpression of TGFα in transgenic mice results in hyperplasia of the anterior prostate.114 Whereas TGFα has been shown to be a growth stimulator that may be critical in the cellular proliferation associated with prostatic growth, TGFβ3 may be an important factor in continued ductal elongation and morphogenesis. The role of TGFβ2 in the developing epithelium, however, remains unclear. In conclusion, the cascade of events starting with the onset of testosterone production by the fetal testes, the expression of functional androgen receptors, and the conversion of testosterone to DHT by 5α-reductase all modulate the differential expression of peptide growth factors in both prostatic mesenchyme and the epithelial cells.140 All the data taken together support the role of peptide growth factors as local mediators that, by autocrine and paracrine pathways, may be directly responsible for mesenchymal and epithelial interactions leading to human fetal prostate development. Further studies are required in the growing prostate to elucidate the differences in growth factor expression in the growing versus the normal growth-quiescent adult prostate. Recent advances in prostate development Shapiro et al.157 studied prostate development in human male fetuses with myelomeningocele (MMC) at 20 weeks’ gestational age. Immunohistochemical staining was performed using Masson’s trichrome and antibodies to smooth and skeletal muscle actin. S-100 protein for
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Page 22 Schwann cell localization and neurofilament protein was also used. These studies demonstrated a marked decrease in the peripheral neural innervation to the prostate in MMC. Trichrome and smooth muscle actin staining also showed that smooth muscle in MMC specimens was less well differentiated. Prostatic size, ductal morphogenesis, and smooth muscle were decreased when compared to controls. At the level where the ejaculatory ducts enter into the prostatic urethra, the mean cross-sectional area was 6.79 mm2 and 11.91 mm2 in the MMC and normal prostate, respectively. Control prostates showed smooth muscle surrounding acini which subsequently become cannulated. In MMC prostates, smooth muscle was absent in the periphery where ductal branching and formation of acini normally occur. They concluded that there is a global defect in the development of smooth muscle in MMC prostate at 20 weeks’ gestation. Since the peripheral nerve density was diminished in the MMC prostate, an intact nervous system may be important in the smooth muscle and ductal morphogenesis of the developing prostate. Xue et al.158 examined chromogranin-A and serotonin immunostaining in 42 prostates, from fetuses at 12–38 weeks’ gestation, infants, prepubertal males and young adults. They determined the staining neuroendocrine (NE) cell index by evaluating the number of epithelial cells and NE cells in tissue sections. They determined that, from 13 weeks’ gestation, NE cells were detected in the prostate. By 20 weeks, all prostates contained NE cells. NE cells were identified mainly in the acinous/ductal regions, whereas most budding tips were devoid of NE cell staining. There were no significant differences found between any of the age groups studied. This study suggests that NE cells may have a role in differentiation and ductal morphogenesis. The NE cells are preferentially distributed in the acinous/ductal region, which may imply a paracrine function during secretory differentiation of exocrine epithelial cells. Cytokeratins have been used to identify various epithelial cells. In 1991, Sherwood et al. identified cytokeratins associated with the basal and luminal epithelia of the human prostate.159 Monoclonal anticytokeratin 8.12 was shown to exhibit immunoactivity with basal but not luminal epithelia. There was no 8.12 antibody staining since prostate cancer tissues are devoid of basal cells. Epithelia of 30 and 36 weeks’ gestation prostates contained only basal cells, whereas both luminal and basal cells were noted in 7-month- and 1-year-old juvenile prostates. This finding has suggested a stem cell function for the prostatic basal cells. Xue et al.160 recently examined keratin expression in the developing human prostate. Samples from five fetuses (of 17, 19, 27, 32, and 38 weeks’ gestation), three infants, three prepubertal males, and one 11-year-old male were studied. They found that, in the early stages of prostate development, cells with an intermediate keratin phenotype can be identified. There were large numbers of these cells, which suggests a hierarchical pathway of cellular differentiation from basal to luminal cells. Intermediate cells were identified by their coexpression of antibodies to RC K103, which recognizes K5 found in basal cells and K18 which is found in luminal cells. In this study there was a variable differentiation-specific keratin in the immature prostate. Their keratin phenotype was K14/K5/K18, which is similar to that of spindleshaped basal cells in the adult prostate.17,18 Interestingly, the luminally located cells were partially positive for 34-βE12 and RCK103, which both stain for basal cells, and almost all contained K18. This suggests that luminally located cells are not fully differentiated and that they still have basal cell and intermediate cell characteristics. Bierhoff et al.161 examined morphological analogies of fetal prostate stroma and nodular stromal proliferates in BPH. The fetal prostates ranged in age from 12 to 40 weeks of gestation. They showed that the developing fetal prostate stroma consists of immature mesenchymal cells up to 17 weeks of gestation, followed by fibroblastic and fibromuscular stromal cells up to week 25 of gestation and predominantly smooth muscle cells until the end of gestation. Stromal nodules occur as immature mesenchymal, fibroblastic, fibromuscular, and smooth muscular, suggestive of a maturational process. The fetal prostate stroma and the stromal nodules present with an increasing degree of maturation, a similar vascular pattern, and a similar occurrence of CD3 (2 lymphocytes), CD20 (B lymphocytes), CD68 (macrophages), S100, and neuron-specific enolase-positive cells. These data suggest that ontogenic processes are recapitulated in the development of stromal nodules in BPH, supporting the idea of the reawakening of fetal processes in BPH. Summary The fetal prostate represents the most proliferative state of the prostate. Over the past 5 years, a great deal has been learned about the molecular events associated with fetal prostate development. Unraveling the mechanisms of fetal prostate growth and development is likely to have important implications for understanding the mechanism giving rise to BPH and prostate cancer, two important diseases of aberrant growth of the prostate. file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_22.html[09.07.2009 11:51:26]
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Page 23 References 1. Stephens F D. Congenital malformations of the urinary tract. New York: Praeger, 1993 2. Hamilton W J, Mossman H W. The urogenital system. In: Human embryology: prenatal development of form and function, 4th edn. New York: Macmillan, 1976:201 3. McNeal J E. The prostate and prostatic urethra: a morphologic synthesis. J Urol 1972; 107:1008 4. McNeal J E. Development and comparative anatomy of the prostate. In: Grayhack J T, Wilson J D, Scherbenske MJ (eds). Benign prostatic hyperplasia. Bethesda: DHEW Publication No NIH 76–1113, Washington: US Government Printing Office, 1976:1 5. Johnson F P. The later development of the urethra in the male. J Urol 1920, 4:447 6. Kellokumpu-Lehtinen P. The histochemical localization of acid phosphatase in human fetal urethral and prostatic epithelium. Invest Urol 1980; 17:435–440 7. Kellokumpu-Lehtinen P. Development of sexual dimorphism in human urogenital sinus complex. Biol Neonate 1985; 48:157 8. Kellokumpu-Lehtinen P, Santti R, Pelliniemi L J. Correlation of early cytodifferentiation of the human fetal prostate and leydig cells. Anat Rec 1980; 196:263–273 9. Lowsley O S. The development of the human prostate gland with reference to the development of other structures at the neck of the urinary bladder. Am J Anat 1912; 13:299–346 10. Pointis G, Latreille M T, Cedard L, Gonado-pituitary relationships in the fetal mouse at various times during sexual differentiation. J Endocrinol 1980; 86:48 11. Resko J A. Androgen secretion by the fetal and neonatal Rhesus monkey. Endocrinology 1978; 87:680 12. Siiteri P K, Wilson J D. Testosterone formation and metabolism during male sexual differentiation in the human embryo. J Clin Endocrinol Metab 1974; 38:113 13. Weniger J P, Zeis A. Sur la secretion prococe de testosterone par le testicule embryonnaire de souris. Comp Rend Acad Sci Paris 1972; 275:1431 14. Winter J S D, Faiman C, Reyes F. Sexual endocrinology of fetal and perinatal life. In: Austin CR, Edward RG (eds). Mechanisms of sex differentiation in animal and man. New York: Academic Press, 1981:205 15. Cunha G R. Epithelio-mesenchyme interactions in primordial gland structures which become responsive to androgenic stimulation. Anat Rec 1972; 172:179 16. Wilson J D, Griffin J E, Leshin M et al. Role of gonadal hormones in development of the sexual phenotypes. Hum Genet 1981; 58:78 17. Franks L M. Benign nodular hyperplasia of the prostate. A review. Ann R Coll Surg Engl 1954; 14:92–106 18. Franks L M. Benign prostatic hyperplasia. Gross and microscopic anatomy. In: Grayhack J T, Wilson J D, Scherbenske M K (eds). Benign prostatic hyperplasia. NIAMDD Workshop Proceedings, 20–21 Feb, 1975. DHEW Publication No NIH 76–1113. Washington: US Government Printing Office, 1976:63–89 19. Zondek T, Zondek L H. The fetal and neonatal prostate. In: Goland M (ed). Normal and abnormal growth of the prostate. Springfield: CC Thomas, 1975:5–28 20. Xia T, Blackburn W R, Gardner W A. Fetal prostate growth and development. Pediatr Pathol 1990; 10: 527–537 21. Popek E J, Tyson R W, Miller G J, Caldwell S A. Prostate development in prune belly syndrome and posterior urethral valves: etiology of PBS—lower urinary tract obstruction or primary mesenchymal defect? Pediatr Pathol 1991; 11:1–29 22. Shapiro E, Hartanto V, Becich M L, Lepor H. The relative proportion of stromal and epithelial hyperplasia is related to the development of symptomatic BPH. J Urol 1992; 147:1293 23. Shapiro E, Hartanto V, Lepor H. Quantifying the smooth muscle content of the prostate using double-immunoenzy-matic staining and color assisted image analysis. J Urol 1992; 147:1167–1170 24. Andrews G S. The histology of the human fetal and prepubertal prostates. J Anat 1951; 85:44–54 25. Shapiro E, Perlman E, Hartanto V et al. Morphometric analysis of pediatric and non-hyperplastic prostate glands: evidence that BPH is not a unique stromal process. Prostate 1997; 33:177–182 26. Rajfer J, Coffey D S. Sex steroid imprinting of the immature prostate: long-term effects. Invest Urol 1978; 16: 186–190 27. Naslund M J, Coffey D S. The differential effects of neonatal androgen, estrogen, and progesterone on adult rat prostate. J Urol 1986; 136:1136–1140 28. Timms B G, Mohs T J, Didio L J A. Ductal budding and branching patterns in the developing prostate. J Urol 1994; 151:1427–1432 file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_23.html[09.07.2009 11:51:26]
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McNeal McNeal McNeal McNeal
J J J J
E. E. E. E.
The zonal anatomy of the prostate. Prostate 1981; 2:35–49 The prostate gland: morphology and pathology. Monogr Urol 1983; 4:3 The prostate gland: morphology and pathobiology. Monogr Urol 1988; 9:3 Normal histology of the prostate. Am J Surg Pathol 1988; 12:619
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Page 24 33. Egevad L. Cytology of the central zone of the prostate. Diagn Cytopathol 2003; 28:239–244 34. Zlotta A R, Djavan B, Damoun M et al. The importance of measuring the prostatic transition zone: an anatomical and radiological study. BJU Int 1999; 84:661–666 35. Islam M A, Kato H, Hayama M. Are neuroendocrine cells responsible for the development of benign prostatic hyperplasia? Eur Urol 2002; 42:79–83 36. Crescioli C, Villari D, Forti G et al. Des (1–3) IGF-I-stimulated growth of human stromal BPH cells is inhibited by a vitamin D(3) analogue. Mol Cell Endocrinol 2002; 198: 69–75 37. Farnsworth W E. Prostate stroma: physiology. Prostate 1999; 38:60–72 38. Niu Y, Xy Y, Zhang J et al. Proliferation and differentiation of prostatic stromal cells. BJU Int 2001; 87:386–393 39. Cunha G R. The role of androgens in the epithelio-mesenchymal interactions involved in prostatic morphogenesis in embryonic mice. Anat Rec 1972; 175:87 40. Cunha G R. Support of normal salivary gland morphogenesis by mesenchyme derived from accessory sexual glands of embryonic mice. Anat Rec 1972; 173:205 41. Cunha G R. Epithelial-stromal interactions in development of the urogenital tract. Int Rev Cytol 1976; 47: 137–194 42. Cunha G R, Lung B. The possible influences of temporal factors in androgenic responsiveness of urogenital tissue recombinants from wild-type and androgen-insensitive (Tfm) mice. J Exp Zool 1978; 205:343 43. Cunha G R, Chung L W K, Shannon J M, Reese B A. Stromal-epithelial interactions in sex differentiation. Biol Reprod 1980; 22:19–43 44. Cunha G R, Chung L W K. Stromal-epithelial interactions: induction of prostatic phenotype in urothelium of testicular feminized (Tfm/y) mice. J Steroid Biochem 1981; 14:1317 45. Cunha G R, Chung L W K, Shannon J M et al. Hormoneinduced morphogenesis and growth: role of mesenchy-mal-epithelial interaction. Recent Prog Horm Res 1983; 39:559–598 46. Cunha G R, Donjacour A A. Stromal-epithelial interactions in normal and abnormal prostatic development. Prog Clin Biol Res 1987; 239:251–272 47. Cunha G R, Donjacour A A, Cooke P S et al. The endocrinology and developmental biology of the prostate. Endocr Rev 1987; 8:388 48. Cunha G R, Donjacour A A. Mesenchymal-epithelial interaction in the growth and development of the prostate. In: Lepor H, Ratliff TL (eds). Urologic oncology. Boston: Kluwer Academic, 1989:159 49. Cunha G R, Alarid E T, Turner T et al. Normal and abnormal development of the male urogenital tract: role of androgens, mesenchymal-epithelial interactions, and growth factors. J Androl 1992; 13:465 50. Cunha G R, Hayward S W, Wang Y Z. Role of stroma in carcinogenesis of the prostate. Differentiation 2002; 70: 473–85 51. Donjacour A A, Cunha G R. The effect of androgen deprivation on branching morphogenesis in the mouse prostate. Dev Biol 1988; 128:1 52. Burns R K. Role of hormones in the differentiation of sex. In: Young WC (ed). Sex and internal secretions. Baltimore: Williams & Wilkins, 1961:76 53. Elger W, Graf K J, Steinbeck H et al. Hormonal control of sexual development. Adv Biosci 1974; 13:41 54. Greene R R. Hormonal factors in sex inversion. The effects of sex hormones on embryonic sexual structures of the rat. Biol Symp 1940; 9:105 55. Greene R R, Burrill M W, Ivy A C. The effects of estrogens on the antenatal sexual development of the rat. Am J Anat 1939; 67:305 56. Jost A. Problems of fetal endocrinology: the gonadal and hypophyseal hormones. Recent Prog Horm Res 1953; 8: 379–418 57. Neumann F, Elger W, Steinbeck H. Antiandrogens and reproductive development. Phil Trans R Soc Long (Biol) 1970; 25:179 58. Neumann F, Graf K J, Elger W. Hormone-induced disturbances in sexual differentiation. Adv Biosci 1974; 13:71 59. Raynaud A, Frilley M. Destruction de cerveau des embryos de souris au treizieme jour de la gestation, par irradiation au moyen des rayon X. Comp Rend Soc Biol 1947; 141:658 60. Wilson J D. Androgens. In: Hardman J G, Limbird LE (eds). Goodman & Gilman’s The pharmacological basis of therapeutics, 10th edn. New York: McGraw-Hill, 2001: 1441–1458 61. Lung B, Cunha G R. Development of seminal vesicles and coagulating glands in neonatal mice 1: The morphogenetic effects of various hormonal conditions. Anat Rec 1981; 199:73 file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_24.html[09.07.2009 11:51:27]
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62. Price D. Normal development of the prostate and seminal vesicles of the rat with a study of experimental postnatal modifications. Am J Anat 1936; 60:79 63. Sherwood J B, McConnell J D, Vazquez D J et al. Heterogeneity of 5 alpha-reductase gene expression in benign prostatic hyperplasia. J Urol 2003; 169:575–579 64. Steers W D. 5 Alpha-reductase activity in the prostate. Urology 2001; 58 Suppl 6:17–24 (discussion 24) 65. Imperato-McGinley J, Binienda Z, Arthur A et al. The development of a male pseudohermaphroditic rat using an
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Page 25 inhibitor of the enzyme 5α reductase. Endocrinology 1985; 116:807 66. Imperato-McGinley J, Guerrero L, Gautieer T et al. Steroid 5α-reductase deficiency in man. An inherited form of pseudohermaphroditism. Science 1974; 186:1213 67. Walsh P C, Madden J D, Harrod M J et al. Familial incomplete male pseudohermaphroditism type 2: decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med 1974; 291:944 68. Griffin J E, Wildon J D. Disorders of sexual differentiation. In: Walsh P C, Gittes R F, Perlmutter A D et al. (eds). Campbell’s urology, 5th edn. Philadelphia: WB Saunders, 1986:1819 69. Ohio S. Major sex determining genes. New York: Springer-Verlag, 1979:1–140 70. Lasnitzki I, Mizuno T. Prostatic induction and interaction of epithelium and mesenchyme from normal wild-type and androgen-insensitive mice with testicular feminization. J Endocrinol 1980; 85:423 71. Shannon J M, Cunha G R. Autoradiographic localization of androgen binding in the developing mouse prostate. Prostate 1983; 4:367–673 72. Shannon J M, Cunha G R, Vanderslice K D. Autoradiographic localization of androgen receptors in the developing urogenital tract and mammary gland. Anat Rec 1981; 199:232 73. Takeda H, Mizuno T, Lasnitzki I. Autoradiographic studies of androgen-binding sites in the rat urogenital sinus and postnatal prostate. J Endocrinol 1985; 104:87–92 74. Wasner G, Hennermann I, Kratochwil K. Ontogeny of mesenchymal androgen receptors in the embryonic mouse mammary gland. Endocrinology 1983; 113:1771 75. Sugimura Y, Cunha G R, Donjacour A A. Morphogenesis and histologic study of castration-induced degeneration and androgen-induced regeneration in the mouse prostate. Biol Reprod 1980; 22:19–43 76. Hayashi N, Sugimura Y, Kawamura J et al. Morphological and functional heterogeneity in the rat prostate gland. Biol Reprod 1991; 45:308–321 77. Bazer G T. Basal cell proliferation and differentiation in regeneration of the rat ventral prostate. Invest Urol 1979; 17:470 78. Ichihara I, Pelliniemi L J. Ultrastructure of the basal cell and the acinar capsule of rat ventral prostate. Anat Anz 1975; 138:355 79. Dahl E, Kjaerheim A, Tveter K. The ultrastructure of the accessory sex organs of the male rat. 1. Normal structure. Z Zellforsch 1973; 137:345 80. Timms B G, Chandler J A, Sinowatz F. The ultrastructure of basal cells of rat and dog prostate. Cell Tissue Res 1976; 173:542 81. Rowlatt C, Franks L M. Myoepithelium in mouse prostate. Nature 1964; 202:707 82. Lee C, Sensibar J, Dudek S et al. Prostatic ductal system in rats: regional variation in morphological and functional activities. Biol Reprod 1990; 43:1079–1086 83. Sensibar J, Griswold M, Sylvester S et al. Prostatic ductal system in rats: regional variation in localization of an androgen-repressed gene product, sulfated glycoprotein-2. Endocrinology 1991; 128:2091–2102 84. Rouleau M, Legert J, Tenniswood M. Ductal heterogeneity of cytokeratins, gene expression, and cell death in the rat ventral prostate. Mol Endocrinol 1990; 4:2003–2013 85. Aumuller G. Morphologic and endocrine aspects of prostatic function. Prostate 1983; 4:195 86. English H F, Drago J R, Santen R J. Cellular response to androgen depletion and repletion in the rat ventral prostate; autoradiography and morphometric analysis. Prostate 1985; 7:41 87. Brandes D. Fine structure and cytochemistry of male accessory organs. In: Brandes D (ed). Male accessory sex organs: structure and function. New York: Academic Press, 1974:18 88. Marker P C, Donjacour A A, Dahiya R, Cunha G R. Hormonal, cellular, and molecular control of prostatic development. Dev Biol 2003; 253:165–174 89. Berry S, Isaacs J T. Comparative aspects of prostatic growth and androgen metabolism with aging in the rat versus the dog. Endocrinology 1984; 114:511 90. Cooke P S, Young P, Cunha G R. Androgen receptor expression in developing male reproductive organs. Endocrinology 1991; 128:2867 91. Prins G, Cooke P, Birch L et al. Androgen receptor expression and 5α reductase activity along the proximal-distal axis of the rat prostate duct. Endocrinology 1992; 130: 3066–3073 92. Prins G S, Birch L. The developmental pattern of androgen receptor expression in rat prostate lobes is altered after neonatal exposure to estrogen. Endocrinology 1995; 136:1303–1314 93. Prins G. Neonatal estrogen exposure induces lobe-specific alterations in adult rat prostate and androgen receptor expression. Endocrinology 1992; 130:3703–3714 file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_25.html[09.07.2009 11:51:27]
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94. Sar M, Welsch F. Oestrogen receptor alpha and beta in rat prostate and epididymis. Andrologia 2000; 32:295–301 95. Cooke P S, Young P, Hess R A, Cunha G R. Estrogen receptor expression in developing epididymis, efferent ductules, and other male reproductive organs. Endocrinology 1991; 128:2874–2879 96. Donjacour A A, Cunha G R. Assessment of prostatic protein secretion in tissue recombinants made of urogenital sinus mesenchyme and urothelium from normal or andro-
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Page 26 gen-insensitive mice. Endocrinology 1993; 132: 2342–2350 97. Cunha G R, Battle E, Young P et al. Role of epithelial-mesenchyme interaction in the differentiation and spatial organization of visceral smooth muscle. Epithelial Cell Biol 1992; 1:76–83 98. Aaronson S A, Bottaro D P, Miki T et al. Keratinocyte growth factor: a fibroblast growth factor family member with unusual target cell specificity. Ann NY Acad Sci 1991; 638:62–77 99. Nilsen-Hamilton M. Transforming growth factor-β and its actions on cellular growth and differentiation. Curr Top Dev Biol 1990; 24:95–136 100. Partanen A M. Epidermal growth factor and transforming growth factor-α in the development of epithelial-mesenchymal organs of the mouse. Curr Top Dev Biol 1990; 24:31–55 101. Cunha G R. Role of mesenchymal-epithelial interactions in normal and abnormal development of the mammary gland and prostate. Cancer 1994; 74:1030–1043 102. Norman J T, Cunha G R, Sugimura Y. The induction of new ductal growth in adult prostatic epithelium in response to an embryonic prostatic inductor. Prostate 1986; 8:209–220 103. Steiner M S, Barrack E R. Transforming growth factor-β1 overproduction in prostate cancer: effects on growth in vivo and in vitro. Mol Endocrinol 1992; 6:15 104. Mansson P E, Adams P, Kan M, McKeehan W L. Heparinbinding growth factor gene expression and receptor characteristics in normal rat prostate and two transplantable rat prostate tumors. Cancer Res 1989; 49:2485 105. Connolly J M, Rose D P. Production of epidermal growth factor and transforming growth factor-α by the androgenresponsive LNCaP human prostate cancer cell line. Prostate 1990; 16:209 106. Story M T, Livingston B, Baeten L et al. Cultured human prostate-derived fibroblasts produce a factor that stimulates their growth with properties indistinguishable from basic fibroblast growth factor. Prostate 1989; 15:355 107. Wilding G, Zugmeier G, Knabbe C, Flanders KC, Gelmann E. Differential effects of transforming growth factor beta on human prostate cancer cells in vitro. Mol Cell Endocrinol 1989; 62:79 108. McKeehan W L, Adams P S. Heparin-binding growth factor/prostatropin attenuates inhibition of rat prostate tumor epithelial cell growth by transforming growth factor type beta. In Vitro Cell Dev Biol 1988; 24:243 109. Wilding G, Valverius E, Knabbe C, Gelmann E P. Role of transforming growth factor-α in human prostate cancer cell growth. Prostate 1989; 15:1 110. Shain S A, Lin A L, Koger J D, Karaganis A G. Rat prostate cancer cells contain functional receptors for transforming growth factor-beta. Endocrinology 1990; 126:818 111. Kyprianous N, Isaacs J T. Identification of a cellular receptor for transforming growth factor-beta in rat ventral prostate and its negative regulation by androgens. Endocrinology 1988; 123:2124 112. Muller W J, Lee F S, Dickson C et al. The int-2-gene product acts as an epithelial growth factor in transgenic mice. EMBO J 1990; 9:907 113. Tutrone R F, Ball R A, Ornitz D M et al. Benign prostatic hyperplasia in a transgenic mouse: a new hormonally sensitive investigatory model. J Urol 1993; 149:633 114. Sandgren E P, Luetteke N C, Palmiter R D et al. Overexpression of TGFα in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia and carcinoma of the breast. Cell 1990; 61:1121 115. Katz A E, Benson M C, Wise G J et al. Gene activity during the early phase of androgen-stimulated rat prostate regrowth. Cancer Res 1989; 49:5889 116. Kyprianou N, Isaacs J T. Expression of transforming growth factor-beta in the rat ventral prostate during castration-induced programmed cell death. Mol Endocrinol 1989; 3:1515 117. Avallet O, Vigier M, Perrard-Sapori M H, Saez J M. Transforming growth factor beta inhibits Leydig cell functions. Biochem Biophys Res Commun 1987; 146:575 118. Lin T, Blaisdell J, Haskell J F. Transforming growth factorbeta inhibits Leydig cell steroidogenesis in primary culture. Biochem Biophys Res Commun 1987; 146:387 119. Steiner M S. The role of peptide growth factors in the prostate. A review. Urology 1993; 42:99 120. Fiorelli G, DeBellis A, Longo A et al. Insulin-like growth factor-1 receptors in human hyperplasia prostate tissue: characterization, tissue localization and their modulation by chronic treatment with a gonadotropin-releasing hormone analog. J Endocr Metab 1991; 72:740 121. Kimura G, Kasuya J, Giannini S et al. Inhibition of IGF-II-stimulated growth of prostate cancer cells by IGF-I receptor-specific monoclonal antibody and antisense oligonucleotide of IGF-II messenger RNA. J Urol 1994; 151: 367A (abstract) file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_26.html[09.07.2009 11:51:28]
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122. Saez C, Gonzalez-Baena A C, Japon M A et al. Expression of basic fibroblast growth factor and its receptors FGFR1 and FGFR2 in human benign prostatic hyperplasia treated with finasteride. Prostate 1999; 40:83–88 123. Steiner M S. Review of peptide growth factors in benign prostatic hyperplasia and urologic malignancy. J Urol 1995; 153:1085 124. Taylor T B, Ramsdell J S. Transforming growth factor-α and its receptor are expressed in the epithelium of the rat prostate gland. Endocrinology 1993; 133:1306
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Page 27 125. McKeehan W L, Adams P S, Fast D. Different hormonal requirements for androgen-independent growth of normal and tumor epithelial cells from rat prostate. In Vitro Cell Dev Biol 1987; 23:147 126. Smith E P, Russell W E, French F S, Wilson F M. A form of basic fibroblast growth factor is secreted into the adluminal fluid of the rat coagulating gland. Prostate 1989; 14: 353 127. Marchese C, Rubin J, Ron D et al. Human keratinocyte growth factor activity on proliferation and differentiation of human keratinocytes: differentiation of human keratinocytes: differentiation response distinguishes KGF from EGF family. J Cell Physiol 1990; 144:326 128. Iwamura M, Sluss P M, Casamento J B, Cockett A T K. Insulin-like growth factor I: action and receptor characterization in human prostate cancer cell lines. Prostate 1993; 22:243 129. Matsui Y, Halter S A, Holt J T et al. Development of mammary hyperplasia and neoplasia in MMTVTGF alpha transgenic mice. Cell 1990; 61:1147 130. Halter S A, Dempsey P, Matsui Y et al. Distinctive patterns of hyperplasia in MMTV-TGFα transgenic mice. Characterization of mammary gland and skin proliferations. Am J Pathol 1992; 140:1131 131. Martikainen P, Kyprianou N, Isaacs J T. Effect of transforming growth factor-beta 1 on proliferation and death of rat prostatic cells. Endocrinology 1990; 127:2963–2968 132. Hiramatsu M, Kashimata M, Minami N et al. Androgenic regulation of epidermal growth factor in the mouse ventral prostate. Biochem Int 1988; 17:311 133. McKeenhan W L, Adams P S, Rosser M P. Direct mitogenic effects of insulin, epidermal growth factor, glucocorticoid, cholera toxin, unknown pituitary factors and possibly prolactin, but not androgen, on normal rat prostate epithelial cells in serum-free, primary cell culture. Cancer Res 1984; 44:1998 134. Mori H, Maki M, Oishi K et al. Increased expression of genes for basic fibroblast growth factor and transforming growth factor type beta 2 in human benign prostatic hyperplasia. Prostate 1990; 16:71 135. Story M T, Hopp K A, Meier D A et al. Influence of transforming growth factor β1 and other growth factors on basic fibroblast growth factor level and proliferation of cultured human prostate-derived fibroblasts. Prostate 1993; 22:183 136. Takeda H, Chang C. Immunohistochemical and in-situ hybridization analysis of androgen receptor expression during the development of the mouse prostate gland. J Endocrinol 1991; 129:83 137. Tenniswood M. Role of epithelial-stromal interactions in the control of gene expression in the prostate: an hypothesis. Prostate 1986; 9:375 138. Chang S M, Chung L W K. Interaction between prostatic fibroblast and epithelial cells in culture: role of androgen. Endocrinology 1989; 125:2719 139. Story M T. Polypeptide modulators of prostatic growth and development. Cancer Surv 1991; 11:123 140. Raghow S, Shapiro E, Steiner M S. Immunohistochemical location of TGF-α during early human fetal prostate development. J Urol; in press 141. Reyes F I, Boroditsky R S, Winter J S D et al. Studies on human sexual development. II. Fetal and maternal serum gonadotropin and sex steroid concentrations. JCEM 1973; 38:612 142. Alarid E T, Cunha G R, Young P et al. Evidence for a possible organ- and sex-specific role of bFGF in the development of the fetal mammalian reproductive tract. Endocrinology 1991; 129:2148 143. Shapiro E, Tang R, Wang B et al. The expression of 5α-reductase and the androgen receptor in the human fetal prostate. J Urol 1996; 155:534 (abstract) 144. George F W, Peterson K G. 5α-Dihydrotestosterone formation is necessary for embryogenesis of the rat prostate. Endocrinology 1988; 122:1159 145. George F W, Russell D W, Wilson J D. Feed-forward control of prostate growth: dihydrotestosterone induces expression of its own biosynthetic enzyme, steroid 5α-reductase. Proc Natl Acad Sci USA 1991; 88:8044 146. Bermann D M, Tian H, Russell D W. Expression and regulation of steroid 5α-reductase in the urogenital tract of the fetal rat. Mol Endocrinol 1995; 9:1561 147. Imperato-McGinley J, Gautier T, Zirinsky K. Prostate visualization studies in males homozygous and heterozygous for 5α reductase deficiency. J Clin Endocrinol Metab 1992; 75:1022 148. Cunha G R, Donjacour A A. Mesenchymal-epithelial interaction in the growth and development of the prostate. In: Lepor H, Ratliff T L (eds). Urologic oncology. Boston: Kluwer Academic Publishers, 1989 149. Hayward S W, Baskin L S, Haughney P C et al. Epithelial development in the rat ventral prostate, anterior prostate and seminal vesicle. Acta Anat 1996; 155:81 150. Hayward S W, Baskin L S, Haughney P C et al. Stromal development in the ventral prostate, anterior prostate and seminal vesicle of the rat. Acta Anat 1996; 155:94 151. Takeda H, Suematso N, Mizuno T. Transcription of prostatic steroid binding protein (PSBP) gene is induced by epithelial-mesenchymal interaction. Development 1990; 110:273 file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_27.html[09.07.2009 11:51:28]
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152. Coffey R J, Derynck R, Wilcox J N et al. Production and auto-induction of transforming growth factor-β in human keratinocytes. Nature 1987; 328:817
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Page 28 153. Derynck R, Lindquist P B, Bringman T S et al. Expression of the transforming growth factor-alpha gene in tumor cells and normal tissue. Cancer Cells 1989; 7:297 154. Lee D C, Rochford R M, Rodaro G J et al. Developmental expression of rat transforming growth factor-α mRNA. Mol Cell Biol 1985; 5:3644 155. Samsoonder J, Kobrin M S, Kudlow J E. Transforming growth factor-a secreted by untransformed bovine anterior pituitary cells in culture. J Biol Chem 1986; 261: 14 408–14 413 156. Skinner M K, Takacs K, Coffey R J. Transforming growth factor-a gene expression and action in the seminiferous tubule. Peritubular cell-Sertoli cell interactions. Endocrinology 1989; 124:845 157. Shapiro E, Seller M J, Lepor H et al. Altered smooth muscle development and innervation of the lower genitourinary and gastrointestinal tract of the human male fetus with myelomeningocele. J Urol 1998; 160:1047 158. Xue Y, Smedts F, van der Laak J et al. The neuroendocrine cell in the developing human prostate. J Urol 1999; 161: 56 (abstract # 209) 159. Sherwood E R, Theyer G, Steiner G et al. Differential expression of specific cytokeratin polypeptides in the basal and luminal epithelia of the human prostate. 1991; 18: 303 160. Xue Y, Smedts F, Debruyne F M J, de la Rosette J, Schalken J A. Identification of intermediate cell types by keratin expression in the developing human prostate. Prostate 1998; 34:292 161. Bierhoff E, Walljasper U, Hofmann et al. Morphological analogies of fetal prostate stroma and stromal nodules in BPH. Prostate 1997; 31:234
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Page 29 3 Molecular control of prostatic growth A Turkes K Griffiths Introduction Our knowledge and understanding of the endocrine, biochemical, and molecular processes implicated in the pathogenesis of prostatic disease are rapidly growing. Although it would now be recognized that symptomatic clinical benign prostatic hyperplasia (BPH), associated with bladder outlet obstruction, is not a premalignant condition that leads to the development of prostatic cancer, current thought tends to be directed to the possibility that the earlier stages in the natural history of BPH, essentially related to epithelial cell hyperplasia and microscopic BPH, may well give rise to transition zone cancer.1 Prostatic enlargement associated with bladder outlet obstruction is generally the end result of dysfunctional growth regulatory mechanisms within the gland, that can result in the development of a benign stromal adenoma (Fig. 3.1). It is also clear from our understanding that the clinical manifestations of symptomatic BPH are generally recognized in men over the age of 50 years. Indeed, the aging factor is considered a risk factor relating to the disease. Also now accepted, is the evidence that a large proportion of men in their later years will have some degree of prostate enlargement,2,3 often causing bladder outlet obstruction that requires surgical intervention. Moreover, as life expectancy is extended around the world, it would be expected that the proportion of men requiring a transurethral prostatectomy will consequently increase, and it is currently predicted that in the USA, for example, a man of 40 years of age now has a 30% chance of under-going such surgical treatment in his lifetime.4 Twenty-five years ago, approximately 10% could be expected to have surgery.5 Although surgery in the form of transurethral resection of the prostate offers effective therapy for bladder outlet obstruction, the extensive and increasing use of medical treatment, α-blockers and 5αreductase inhibitors, for the management of BPH is now well
Figure 3.1 Obstruction to urinary flow.
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Page 30 recognized. The use of 5α-reductase inhibitors suppresses the conversion of testosterone to 5αdihydrotestosterone (DHT), the principal ‘active androgen’ within the prostate gland. Concurrently, intense research activity is attempting to improve understanding of the molecular processes through which DHT influences prostatic growth and function.6,7 It is noteworthy that clinical BPH occurs during a period of time when testicular function is declining and the concentrations of testosterone in plasma (Fig. 3.2), and also in saliva (Fig. 3.3), are falling with increasing age.8,9 Despite this, most of the related evidence tends to indicate that androgens are implicated in the pathogenesis of the disease. Early castration, or hypopituitarism, appears to prevent the development of BPH. Furthermore, the enlarged prostate regresses following castration or after the administration of luteinizing hormone-releasing hormone (LH-RH) treatment, or after treatment with anti-androgens.10 Plasma hormones, the prostate, and aging Although the prostate grows and functions within a multihormonal environment, responding to a range of regulatory factors, the functional activity of the human gland is primarily dependent on the maintenance of normal concentrations of plasma testosterone. Approximately 90–95% of the 6–7 mg testosterone that is produced daily and appears in the plasma is synthesized by the Leydig cells of the testes,11,12 under the control of LH. The remainder originates in the adrenal gland, either by direct synthesis and secretion or from its production by the peripheral metabolism of the adrenal androgens, the C19 steroids dehydroepiandrosterone (DHA), DHA sulfate, or androstenedione, by muscle and adipose tissue (Fig. 3.4). The concentration of testosterone in the spermatic vein is approximately 75 times higher than that in the peripheral venous plasma. LH secretion by the pituitary
Figure 3.2 Decline in the concentration of testosterone in plasma with increasing age. (Data from Riad-Fahmy et al. 8)
Figure 3.3 Range of salivary testosterone concentrations in a large population of males of different ages. The salivary steroid concentration represents the plasma levels of free, nonprotein-bound, biologically active steroid moiety. The concentrations decline significantly with age.
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Figure 3.4 Testosterone (T) production by the human male. LH, luteinizing hormone; RH, releasing hormone; ACTH, adrenocorticotropic hormone; SHBG, sex hormone-binding globulin. gland is controlled by LH-RH, a decapeptide released by the hypothalamus in a pulsatile manner, thereby promoting a similar, corresponding pulsatile secretion of LH. Both the androgens and estrogens are involved in negative feedback control processes in order to regulate LH synthesis and secretion.13 In man, approximately 30% of the plasma estrogens are synthesized and secreted by the testes,14,15with the major proportion, however, being produced by the peripheral aromatization of androstenedione and testosterone (Fig. 3.5).16 The secretion of the adrenal androgens is controlled by adrenocorticotropic hormone (ACTH), although prolactin may exercise a synergistic influence with ACTH. Testosterone would be considered the most important plasma androgen, but it is the concentration of the free, nonprotein-bound form (Fig. 3.6) which is generally accepted as the biologically active moiety that enters the prostate target cells. The free testosterone level normally provides a reasonable indicator of the androgenic status of the male. In the plasma of the younger man,17–20 approximately 57% of the testosterone is specifically and avidly bound to sex hormone-binding globulin (SHBG), with about 40% less well bound to albumin. A smaller amount, 1%, is bound to corticosteroid-binding globulin (CBG) and approximately 2% constitutes the free fraction (Fig. 3.6). The estrogens are similarly bound to SHBG with, again, approximately 2% in the free fraction. SHBG is synthesized and secreted by the liver by processes regulated to some extent by estrogens, with the thyroid hormones and insulin also implicated.21–23 The decline in testicular function with age would generally be considered to be of primary testicular origin.9 Although plasma levels of LH rise in the elderly man, there is also an impaired testicular response to LH and, moreover, a decreasing number of Leydig cells with increasing age, with a consequent fall in plasma testosterone concentrations (Fig. 3.2). Aging generally increases SHBG levels, giving rise to a corresponding reciprocal decrease in the free testosterone concentration. Therefore, although the total plasma testosterone level of an 80-year-old man is approximately 30–40% of that of a 25-year-old, the free concentration represents only 15–20% of that of the younger man (Fig. 3.6). The ‘active’ androgenic steroid hormone within the prostate gland is DHT,24,25 synthesized from testosterone by the 5α-reductase enzyme system located on the nuclear membrane of prostatic cells file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_31.html[09.07.2009 11:51:30]
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(Fig. 3.7). It is interesting that testosterone and DHT are also synthesized from the adrenal androgens within prostatic tissue (Fig. 3.8),26,27 and this particular source of DHT has been implicated by some in the progression of disseminated prostatic cancer after primary endocrine therapy such as castration or the administration of LH-RH analogs.28–30 Studies in animals certainly suggest that the adrenal steroids can influence prostatic growth and function,31 but they cannot restore the size nor maintain the morphology of the prostate of the castrated rat. The significance of the role of the adrenal androgens in the normal prostate has yet to be clarified and, at present, there are few if any data from man to indicate that they are involved in the pathogenesis of BPH. Of interest and rarely considered is that certain of the metabolites of DHT, the 5α-androstanediols, and androst-5-ene-3β,17β-diol, a metabolite of DHA, elicit weak estrogenic effects32 by binding to the estrogen receptor protein (ER) and promoting certain biological responses similar to, but weaker than those effected by estradiol (Fig. 3.8). There is some controversy as to the precise changes in the endocrine status of the male as he ages.6,7,33,34 It is reported that as testicular function declines with
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Figure 3.5 Production of estrogens by the human male: E1, estrone; E2, estradiol-17 β; T, testosterone; LH, luteinizing hormone; ACTH, adrenocorticotropic hormone; DHA, dehydroepiandrosterone; S, sulfate; A, androstenedione; SHBG, sex hormone-binding globulin.
Figure 3.6 Factors concerned with the levels of free, nonprotein-bound steroid hormone in plasma that is considered to be the biologically active moiety that enters the target cell E2, estradiol-17 β; T, testosterone; SHBG, sex. hormone-binding globulin; CBG, corticosteroidbinding globulin.
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Figure 3.7 A simple representation of the intracellular processes relating to the binding of DHT (D) to the androgen receptor (AR) and to the dimerization of the DHT-AR complex when binding to the hormone response elements (HRE), the nucleotide recognition sequences on the genome. T, testosterone; TF, transcription factors binding to the DNA adjacent to the DHT-AR complexes. increasing age, there is a corresponding increase in the rate of peripheral aromatization35,36 such that the levels of estradiol in plasma rise relative to those of testosterone. The SHBG binding capacity is reported to increase in the elderly (Fig. 3.9),18,37 possibly in response to the elevated estrogenic status in the older man, the consequent effect seen as an increased ratio of the plasma free estradiol to free testosterone. The aging prostate is therefore subjected to a changing estrogen/androgen balance that would be expected to influence the amounts of the steroid hormones that are transferred into the prostate cell. It is generally accepted that the free steroid is transferred into the prostate cell by a process of passive file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_33.html[09.07.2009 11:51:31]
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diffusion, although there is still much to understand about
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Figure 3.8 Metabolism of the adrenal androgens by the human prostate gland to produce DHT. The DHT is further metabolized to the 5α-androstanediols, which can elicit weak estrogenic effects by association with the ER. E2, estradiol-17 β; T, testosterone; DHA, dehydroepiandrosterone. these biological mechanisms, with reports that the testosterone-SHBG complex specifically binds to receptors on the cell membrane (Fig. 3.10) to activate signal transduction systems.38 Extrinsic and intrinsic factors The prostate gland is androgen dependent and a source of testosterone is necessary for the growth, development, and function of the gland.39 It is, however, the intraprostatic androgen, DHT, a metabolite of testosterone, that preferentially binds to the androgen receptor (AR) as a DHT-AR complex, it associates with specific hormone response elements (HREs) on the genome and, in association with other transcription factors (TFs), modulates the expression of androgen-responsive genes (Fig. 3.7). The molecular biochemistry by which steroid hormone receptor complexes associate with their specific recognition sequences within the promoter region of responsive genes is now better understood.40,41 DHT is essential for prostate growth7,42 and exercises an important role in the regulation of gene activity. It is now recognized that the biological effects of such extrinsic factors on the prostate gland are mediated by various peptide growth-regulatory factors. These growth factors, which are produced by the gland, influence
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Figure 3.9 Diagram illustrating changes that have been recognized in the endocrine status of the middle-aged man. Declining testicular function and decreasing testosterone (T) output are associated with increased peripheral aromatization of adrenal androgens. The elevated estradiol (E2) levels have been implicated in the increased sex hormone-binding globulin (SHBG) binding capacity and the resultant changes in the free E2/free T ratio in plasma, the overall effect giving rise to an enhanced estrogenic influence on the prostate gland. prostate function by promoting inter- and intracellular signaling between and within cell populations, through paracrine, autocrine, and intracrine effects (Fig. 3.11). Paradoxically, therefore, it appears that DHT is essential to but not directly responsible for cellular proliferation and it is the intrinsic growth factors such as epidermal growth factor (EGF), keratinocyte growth factor (KGF), insulin-like growth factors (IGF-I and -II), and fibroblast growth factors (FGFs), which are mitogenic and directly stimulate proliferation. Lee et al.43 highlighted these prostatic interrelationships (Fig. 3.12).
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Figure 3.10 Simple representation of the reported cell membrane receptor that is activated by the testosterone (T)—sex. hormonebinding globulin (SHBG) complex. to promote intracellular cyclic adenosine monophosphate (cAMP) production. E2, estradiol-17 β. Stromal-epithelial interrelationship It is now recognized that the stromal elements of the prostate gland play an important role in regulating various aspects of growth and function.44–47 Essentially, DHT-mediated effects on the stromal compartment produce growth stimulatory factors which induce signal transduction pathways within the epithelial cells and thereby promote growth and differentiation (Fig. 3.13). Considerable interest currently centers on KGF, one of the FGF family and sometimes referred to as FGF-7, which would seem a particularly important growth-promoting factor in the prostate.48–53 It is produced by stromal fibroblasts and exercises a paracrine mitogenic effect on epithelial cells through an FGF receptor protein (FGF-R) localized on the cell membrane. The receptor, FGF-R2-exonIIIb, is a splice variant of the FGFR2(bek) gene, which preferentially recognizes KGF.54 The growth-inhibitory factor, transforming growth factor β (TGFβ), inhibits this action of KGF on the epithelium; however, KGF has no effect on stromal cell proliferation. In contrast, FGF-2, sometimes referred to as basic FGF (bFGF), elicits an autocrine mitogenic action on prostatic stromal cells,55–57 but has no effect on epithelial cells. FGF-2 promotes stromal growth through the FGF-R1 that is encoded by the FGF-R1(flg) gene, normally localized only in the stromal compartment. Both epithelial and stromal cells produce FGF-2,57 however, and it is particularly relevant that an elevated expression of FGF-2 has been associated with BPH.58
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Figure 3.11 A simple representation of factors involved in the regulation of prostatic growth.
Figure 3.12 Extrinsic and intrinsic growth regulatory factors.
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Figure 3.13 Relationship between stromal and epithelial compartments of the prostate gland. DHT, dihydrotestosterone; TGF, transforming growth factor; FGF, fibroblast growth factors; KGF, keratinocyte growth factor. There is accumulating evidence that the FGF family is intimately involved with the growth-regulatory processes of the prostate. The family currently consists of ten members, FGF-1 to FGF-10, sharing 30– 55% amino acid sequence homology, which interact with high-affinity tyrosine kinase receptors encoded by four distinct genes. Alternative splicing, however, generates numerous receptor isoforms and markedly increases the complexity of the ligand-receptor interactions. Acidic FGF (FGF-1) and basic FGF (FGF-2) were the first to be characterized and have been extensively investigated. As described, FGF-2 and FGF-7 may have a role in the induction of BPH. FGF-8 mRNA, on the other hand, has been reported to be overexpressed in 22 (71%) of 31 human prostate cancers studied, significantly correlating with grade, but rarely in BPH.59 Seven protein isoforms of FGF-8 exist and were shown to have different transforming potentials in NIH3T3 cells.60 The FGF-8b isoform has been identified in androgenindependent DU 145 cells61 and could well be implicated in cancer progression. As the rat prostatic Dunning tumors progressed to androgen independence, there was a switch in the expression of FGF-R2 from the IIIb isoform to the IIIc isoform,62 and the latter is preferentially associated with FGF-2. Also noteworthy is that FGF-8 also binds with high affinity to FGF-R2exonIIIc and FGF-R3exonIIIc.63 It remains to be determined whether the interaction of FGF-8 with FGF-R2exonIIIc is important with regard to hormone-refractory prostate cancer in man. It has been reported that FGF-R3exonIIIc is the most prevalent isoform in both the normal prostate gland and in primary prostatic epithelial cell cultures.64 The significance of this report in relation to FGF-8 has yet to be evaluated. The predominant localization of the ‘classical’ estrogen receptor (ERα) in the stromal compartment of the human prostate65 and the promotion of stromal hyperplasia by estrogen66 suggest that estradiol as well as DHT may be synergistically implicated in the production of FGF-2 (Fig. 3.13). Overall, homeostasis and the maintenance of the fine balance between cell proliferation and cell death are the result of complex interactions between growth-stimulatory factors and growth-inhibitory factors (Fig. 3.14), modulated by steroid hormones, with the proteins encoded by the growth-suppressor genes such as the p53 and retinoblastoma (Rb) genes also exercising a role in normal growth regulation. Differences in both epithelial and stromal cell function within the ductal system of the prostate gland As our understanding of the growth regulatory processes of the prostate gland increases, so does the realization that the system is, indeed, complex. The human prostate gland is a branched glandular structure, with 40 to 50 ductal
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Figure 3.14 A simple illustration of growth-regulatory balance modulated by steroid hormones. TGF, transforming growth factor; FGF, fibroblast growth factors; EGF, epidermal growth factor; KGF, keratinocyte growth factor; IGF, insulin-like growth factors. systems, each duct lined with epithelial cells and embedded in a matrix of stromal components.67,68 The studies of Chung Lee et al.69,70 and of Tenniswood et al.71,72 have highlighted the complexity of the interaction between stromal and epithelial compartments. Essentially, there is a regional variation in the functional activity of epithelial cells in different regions of the rat ductal system that relates to corresponding differences in the stromal elements. These regions are described as proximal, intermediate, and distal (Fig. 3.15) relative to their distance from the urethra. The epithelial cells in the distal region are actively proliferating, those in the intermediate segment, the major component, are differentiated and secretory, while those in the proximal region are associated with programmed cell death, or apoptosis. It is perceived that TGFβ, produced by the smooth muscle-like cells prevalent in the underlying stroma in the proximal region, will exercise a prominent role in promoting cell death,73,74 a process that DHT will restrain. DHT and KGF will be predominant in the distal region promoting epithelial cell proliferation. A balance between the influence of DHT, TGFβ, and KGF in the intermediate segment will promote epithelial cell differentiation and a secretory function (Fig. 3.15). The proximal region exclusively expresses the castration-induced protein testosterone-repressed prostate message-2 (TRPM-2), or clusterin, the protein associated with apoptosis and produced under androgen-deprived conditions. These studies also imply a migration of epithelial cells from the distal proliferative region, along the duct, to the proximal segment where apoptosis prevails. These locally regulated cell-cell interactions, with regional heterogeneity in stromal-epithelial interrelationships, must now be recognized. The cells are all exposed to the same level of circulating androgen, yet the different patterns of cellular behavior suggest a variable androgenic stimulus to the cells. The different cell responses relating to the production and action of growth regulatory factors must be seen as pivotal to prostatic growth control. There is also regional stromal heterogeneity,75 with multiple layers of smooth muscle cells in the proximal region and a single layer underlining the distal epithelial cells. TGFβ, directly implicated in apoptosis, is located in the stromal elements, but particularly in the actin-positive smooth muscle cells of the proximal region. Fibroblasts are reported to be evenly distributed throughout the stromal compartment.76,77 It is important to note, however, that in tissue culture, smooth muscle cells and fibroblasts appear to be somewhat interchangeable, which can lead to problems of interpretation of studies of cells in culture. It is also important to note that receptors for both androgen and estrogen have been identified in smooth muscle cells and in fibroblasts,78,79 with estrogens stimulating smooth muscle growth.80–83
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Figure 3.15 Regional variation in the functional activity of epithelial cells. TGF, transforming growth factor; FGF, fibroblast growth factors; KGF, keratinocyte growth factor; DHT, dihydrotestosterone. (Adapted from references 69 and 72.) Intra- and intercellular signaling pathways The interrelationship between the stromal and epithelial compartments of the prostate would appear to be pivotal to the growth regulatory processes of the gland. Our understanding of the inter- and intracellular signaling pathways between and within cells, and the associated intrinsic growth regulatory factors that control these pathways, is rapidly attaining a highly sophisticated and comprehensive level. The basis of our understanding has, to date, been centered on the more simple relationship between glandular epithelial cells and the muscle cells and fibroblasts of the stromal compartment. The prostatic neuroendocrine cells are also located within the epithelial compartment, being basally orientated (Fig. 3.16) and morphologically, either the ‘open type’, with apical processes extending to the lumen, or the ‘closed type’, both having long dendritic processes extending under and weaving between adjacent epithelial cells.84 There is speculation regarding their role, but it generally would be considered to encompass the regulation of cell growth and differentiation as well as neuroendocrine, endocrine, and exocrine secretion.85,86 They are specialized, differentiated cells that contain and secrete: • The biogenic amine, serotonin; • Bombesin/gastrin-releasing peptide; • The chromogranin family of polypeptides; • The calcitonin family of peptides; • Somatostatin; • Parathyroid hormone related protein (PTHrP); • Thyroid-stimulating hormone (TSH)-like peptide; • Human chorionic gonadotropin (HCG)-like peptide. Although the high levels of calcitonin, bombesin, and somatostatin in semen suggest that these peptides are directly secreted by the neuroendocrine cells, little is known about the intercellular autocrine and paracrine local regulatory mechanisms by which the neuroendocrine cells interrelate with the neighboring cells.87 This may involve interaction between neuroendocrine cells, factors produced by the stromal compartment, extrinsic, blood-borne endocrine agents, or an input from the nervous system (Fig. 3.16). There is speculation that neuroendocrine cells are implicated in the focal development of BPH.87 Bombesin, for example, a well-established growth
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Figure 3.16 Morphology of the neuroendocrine cells of the epithelial compartment and some of the intrinsic factors implicated in the interaction between stromal and epithelial compartments of the prostate gland. TGF, transforming growth factor; KGF, keratinocyte growth factor; TSH, thyroid-stimulating hormone; PTH, parathyroid hormone; hCG, human choriogonadotropin; VEGE, vascular endothelial growth factor. factor in the lung in association with small cell carcinoma, also exercises a mitogenic effect on prostatic cancer cell lines.88–91 There are similar reports that calcitonin92 and PTHrP93 elicit similar effects. The serotonin antagonist pindobind inhibits the proliferation of human prostatic PC3 cancer cells in vitro and in vivo,94 suggesting that serotonin may have mitogenic effects within the prostate. Focal neuroendocrine cell differentiation is virtually ubiquitous in carcinoma of the prostate84 and the extent of neuroendocrine cell proliferation correlates with poor prognosis. A report from the Tenovus Cancer Research Centre,95 relating to the production of TGF-α and vascular endothelial growth factor (VEGF) by neuroendocrine cells of the human prostate (Fig. 3.17), is of particular interest. The expression of TGF-α, which mediates its biological action through the EGF receptor, is generally associated with the proliferation of human prostatic cancer cells96,97 and VEGF is now recognized as a powerful promoter of angiogenesis (Fig. 3.18). It is well accepted that once a tumor attains a volume of approximately 2 mm, an improved new blood supply is required for continued growth.98–100 The production of VEGF by the neuroendocrine cells of the tumor may well be a factor associated with the promotion of angiogenesis and cancer progression. Prostatic neuroendocrine cells do not express AR95 and appear to be terminally differentiated, postmitotic cells,101 although the proliferation markers PCNA and Ki-67 and the ‘anti-apoptopic factor’ Bcl-2102 are expressed by neighboring cells. Serotonin is mitogenic in certain tissues103 and, permissively with androgens, may regulate epithelial cell proliferation.104,105 Synergistically with other growth factors, it may exercise an important paracrine role in promoting smooth muscle106 and fibroblast107 mitogenesis. It has been proposed,87,108 therefore, that the production of peptides by neuroendocrine cells may be implicated in the focal pathogenesis of BPH and the early biological changes implicated in early transition zone carcinogenesis. In relation to this, the studies of O’Malley et al.109 indicate that dopamine activates steroid hormone receptors in the absence of steroid, raising the possibility that other biogenic amines such as serotonin may elicit similar responses. It would be presumed that dopamine constitutively activates gene expression through the interaction between the N-terminal A/B activation domains of the AR1 and adjacent coactivators associated with their particular recognition sequences on the genome. In considering the complex interplay between the populations of cells that constitute the microenvironment of
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Figure 3.17 Localization and expression of vascular endothelial growth factor (VEGF) by the neuroendocrine cells of the human prostate gland. Neuroendocrine cells are classically recognized by the expression of chromagranin. the human prostate, the basal cells must not be forgotten. These cells, by their very nature, are less differentiated than the luminal cells and are confined to the base of the epithelium (Fig. 3.19). The cytokeratins, intermediate filament proteins and thereby components of the cytoskeleton, are found in epithelial cells and Schalken et al.110 have demonstrated that their pattern of expression varies according to cell type and degree of differentiation. At least 20 different members of the keratin family are expressed in specific combinations in the various types of epithelial cells, and epithelial phenotypes can be recognized in relation to cell differentiation and function.110 With cytokeratin patterns as markers, Schalken et al.110 showed that withdrawal of androgen reduced the population of luminal epithelial cells, whereas the basal cells were unaffected. The luminal cell number increased appropriately, following testosterone administration. The results suggest a hierarchical relationship between basal and luminal cells, with the basal cells acquiring simple keratins and losing their complex components during differentiation, a concept promulgated by Isaacs and Coffey.111 The stem cell model, essentially relating to the pathogenesis of BPH,111,112 describes a biological system in which the total cell population of the prostate is determined by the number of stem cells. These cells are capable of extensive self-renewal and maintain their proliferative capacity despite any marked change or decrease in the total cell population of the gland.
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Figure 3.18 Promotion of angiogenesis by the vascular endothelial growth factor (VEGF) in neuroendocrine cells. FGF, fibroblast growth factor.
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Figure 3.19 Interrelationship between various cell types, based on keratin phenotypes and differential expression. As depicted by J.Schalken. However, to explain the capacity of the prostate to restore its total cell number after castration and subsequent administration of androgen, Isaacs112 suggested that prostatic cell renewal is not the unique responsibility of this limited number of stem cells. As well as extensive stem cell renewal, it is considered that other ‘amplifying cells’ which originate from stem cells are capable of limited proliferation and are present, with stem cells, in the involuted prostate gland after castration. Despite a limited proliferative capacity, the consequent effect would be seen as an extensive amplification of the total cells produced,112 essentially, a 32-fold increase in cell number on administration of androgen. Prostatic growth would, therefore, result not from any major increase in the rate of stem cell renewal, but from the proliferation of these preexisting amplifying cells. During androgen deprivation, they would independently maintain themselves, but still retain androgen sensitivity. The terminally differentiated ‘transit cells’ formed from this pool of amplifying cells and which equate to the differentiated luminal cells have only limited capacity to proliferate and are androgen dependent. They make up the major proportion of the prostate cell population and are the cells which are lost on androgen withdrawal. Therefore, the earlier stages in epithelial cell proliferation could result from either an increase in stem cell number or from a greater capacity of the amplifying or transit cells to proliferate before cell death or apoptosis. The keratin phenotyping studies of Schalken110 and others113,114 provide a valuable insight into the pathogenesis of prostatic disease and into the complex interrelationships that exist between the various populations of cell types. The balance between cell proliferation and apoptosis In normal tissues, the fine balance between the rate of cell proliferation and that of cell death is tightly controlled. Throughout life, the prostate gland responds to certain extrinsic endocrine signals as it develops during the fetal and prepubertal phases and during the rapid period of growth following adolescence. After attaining its adult size in the early twenties, and with the establishment of homeostasis, the prostate gland normally maintains this size until the age of 50, after which time abnormal growth, both benign and cancerous, is often manifest, presumably because of a disturbance in the regulatory factors controling the balance (Fig. 3.20). The precise nature of the factors that regulate this balance and the genetic or epigenetic factors which are implicated in any imbalance still remain to be determined. Such factors and processes which may exercise an important influence on this homeostatic balance include the various intrinsic growth-regulatory factors and their associated signaling processes, cell cycle regulatory control, damage to DNA, senescence of the cell replication process and the ‘cell death’ genes. However this imbalance occurs, whether it be through an increased rate of cell replication or a decreased rate of cell death, the consequence is an accumulation of
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Figure 3.20 The balance between cell proliferation and cell death in the prostate. prostate cells and an associated growth of the gland. The kinetics of the balance are now being precisely defined in terms of a dynamic interplay between the growth-stimulatory processes and those responsible for growth restraint. The signaling processes that are associated with the cell cycle, and which influence both cell growth and cell death, now constitute one of the most active and particularly exciting fields of scientific research currently being followed, investigations that will have a major impact on our understanding of prostatic growth regulation.115,116 DNA synthesis and cell cycle control The prostatic cell is generally in a quiescent or nongrowing state, that is referred to as G0. The influence of the extrinsic steroid hormones and their interaction with the intrinsic growth regulatory factors which activate cell signaling processes can stimulate a cell to grow and initiate the active phase of the cell cycle, referred to as G1. Once the cell completes this G1 phase it commences DNA synthesis, the S phase of the cycle (Fig. 3.21). Once the DNA has been replicated there is a secondary phase, G2, during which the cell prepares for cell division or mitosis. It is during the mitotic M phase of the cycle that the mitotic spindle of the cell separates into two sets of chromosomes, after which the nucleus reorganizes and the cell cycle is then complete. Clearly, knowledge of the complex processes that regulate the cell cycle is fundamental to understanding prostatic growth control. There are many specific check-points at the interfaces between the various phases of the cycle which determine progression into the next phase. These checkpoints, or decision points as they are called, are controlled by the interaction of a variety of regulatory proteins, referred to as cyclin-dependent kinases (CDKs), which have the capacity to stimulate or suppress the activity of various growth suppressors, by promoting their phosphorylation. Figure 3.21 illustrates the transition of a cell in G0 resting phase to the process of either cell growth or cell death. The cyclin-dependent kinases represent a series of at least seven regulatory enzymes, referred to as CDK2 and CDK4 to CDK7, with their location and the phase in which they influence the cell cycle delineated in Fig. 3.21. They are activated at various points in the cell cycle. An example of the regulatory activity of the cyclindependent kinases involves the activation of a particular specific cell cycle ‘brake’ or growth suppressor protein, the retinoblastoma (Rb) protein. In its nonphosphorylated state, Rb serves as a checkpoint, or brake, between the G1 and S phases of the cell cycle. Activation of the Rb protein through its phosphorylation by a cyclin kinase removes its braking capacity and thereby allows the cell to progress from the G1 phase of the cycle into the S phase, with the resultant initiation of DNA synthesis and promotion of prostatic growth. There are other examples of cyclin-dependent kinase activation involving other cell cycle suppressors. The p15, p16, p21, and p27 proteins are
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Figure 3.21 Regulatory factors in the different phases of the cell cycle. CDC, cell-division cycle; ICE, interleukin converting enzyme; CDK, cyclin-dependent kinases; TGF β-R, transforming growth factor-β receptor; TRPM-2, testosterone-repressed prostate message2; ODC, ornithine decarboxylase. all cycle-independent kinase inhibitors and it is noteworthy that p21 appears to be upregulated by p53. An increased expression of p53 after DNA damage will introduce a brake on the cell cycle, allowing the cell to correct for the damaged DNA. If the p53 protein is damaged, lost, or downregulated, the particular checkpoint is ineffective, allowing uncontrolled growth of the cell, enhanced genetic instability, and DNA damage, cellular characteristics which are inherited by the daughter cells. Control of cell death Also illustrated in Fig. 3.21 are the perceived regulatory checkpoints in the cell-death cycle.115 A celldeath cycle checkpoint D1, a phase analogous to G1 of the cell-growth cycle, is associated with events that occur before DNA fragmentation. The cell-death phase D1 is further subdivided into A and B regions, both of which are regulated by a range of different factors, including interleukin-converting enzyme (ICE), calcium, TGFβ, a particular DNA nuclease, and the TRPM-1 gene, which upregulate this phase of the death cycle. The D1 phase is downregulated through activation of the ornithine decarboxylase (ODC) gene, CDK2, and a cyclin. The next phase of the death cycle, the F phase, is the period of DNA fragmentation and nuclear degradation. During the last D2 phase of the death cycle, which follows DNA fragmentation, the cell finally undergoes nuclear destruction and phagocytosis. The entire cycle has been termed apoptosis, a process which is clearly characterized by significant morphological and biochemical events within the cell. The p53 protein is a regulatory protein that, in certain tissues, is implicated in the control of the celldeath cycle, as is the principal brake of the apoptosis cycle, the bcl-2, a 26-kDa protein. When available and activated, bcl-2 represses the processes associated with cell death. Abnormal, elevated rates of cell death result from a mutation in the bcl-2 gene or from suppression of gene expression. The bcl-2 protein is inhibited from acting as a brake on apoptosis by its association with another protein, referred to as bax, which is a member of a family of celldeath-inducing proteins that have been identified. The bax gene is upregulated by the p53 protein. These interrelationships are simply illustrated in Fig. 3.22. It has been reported that nine out of nine hormonerefractory prostate tumors, or their metastases, expressed bcl-2.116 The bcl-2 gene is also overexpressed in the lesions of preneoplasia referred to as prostatic intraepithelial neoplasia (PIN). Androgen-dependent LNCaP cells, transfected with a vector containing the bcl-2 protooncogene, were resistant, in vitro, to agents which
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Figure 3.22 A simple illustration of the interrelationship between myc, bcl-2, and apoptosis. EGF, epidermal growth factor; FGF, fibroblast growth factor; KGF, keratinocyte growth factor; IGF, insulin-like growth factor. promoted apoptosis.117 Complementary studies in vivo117 showed that when these transfected cells were introduced into nude mice, they developed into larger tumors than the controls and were also resistant to androgen withdrawal, thereby relating bcl-2 expression to the androgenindependent state.118 Quite clearly, the biological processes concerned with the expression and activation of bax and, thereby, the consequent inhibition of bcl-2 and its influence on cell death, must exercise a fundamentally important role in the regulation of prostatic growth. Telomerase and aging: relationship to prostate growth Telomerase and the activity of the telomerase enzyme have recently been recognized as important factors related to growth regulation within the prostate.119–121 The Hayflick phenomenon indicates that cells can undergo only a finite number of cell divisions before they senesce and subsequently destruct through the processes of apoptosis. Cells that do not senesce are termed immortal and, as such, can be established as cell lines in culture. Mortal cells shorten their telomeres, small pieces of DNA located on the ends of chromosomes, with each cell cycle until they become unstable.119 The biological clock that counts each cell division and brings about cell senescence is thus controlled through the telomeres. Each time a cell progresses through a complete cell cycle and divides, it loses a small amount of the telomeric DNA. The repetitive, accumulative loss of these small DNA fragments acts as a ‘mitotic clock’ counting the cell cycles. After approximately 50 doublings, these cells will senesce and die. Telomerase is an enzyme that is concerned with this process on a small template made of RNA that it uses to replace the telomeres after each cell division. If the telomerase is inactive, or depleted from the cell, the telomeres will shorten. If present, the telomeres are relengthened after each cell cycle and immortality can be attained. Studies show that telomerase is a stem-cell marker in the ventral lobe of the rat prostate120 and it is suggested121 that telomerase activity is an effective means of distinguishing benign and malignant growth of the prostate gland (Fig. 3.23). The complex interrelationship between the intrinsic factors within the prostate gland The integrated response of the various populations of cells within the prostate to signaling language, reading sense from the many messages induced by the wide range of growth regulatory factors, as well as those initiated by the extrinsic endocrine factors that impact on the gland, is very clearly a finely tuned and complex interactive system.
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Figure 3.23 Telomerase and the immortality of cells. (Adapted from reference 121.)
Figure 3.24 Tyrosine-specific protein kinase and intracellular signaling pathways. MAPK, mitogen-activated protein kinase; MEK, mitogenactivated protein kinase kinase; TK, tyrosine kinase; KGF, keratinocyte growth factor; Grb2-mSOS, growth factor receptor binding proteinmammalian son-of-sevenless complex; RAF-1, serine-threonine protein kinase; P, protein; PK, protein kinase.
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Page 47 As our understanding of these signaling pathways develops, the information that accumulates provides a greater insight into the potential consequences of their impairment and their relationship to the pathogenesis of prostate disease. Cells which respond to external stimuli such as those induced by KGF or FGF-2 depend not only on the presence of cell membrane-localized receptor proteins (Fig. 3.24), but on the particular activity of the signal transduction pathways, as well as the intracellular structural matrix of the target cell. The nuclear matrix is the cell type-specific framework that is implicated in the organization of DNA and in the biological processes concerned with the regulation of gene transcription.122,123 There is a specific association between the components of the nuclear matrix and steroid hormone receptors in the regulation of gene expression by steroids.124 Fundamental to the hormone responsiveness of the prostate gland is the interrelationship between the signaling pathways inducing biological responses through steroid receptors and those activated by the binding of the peptide growth-regulatory factors to the cell membrane receptors. As described earlier, it would now appear that the mitogenic paracrine effect of DHT on the prostate epithelial cells is mediated by peptide growth-stimulatory factors, probably KGF (FGF-7), produced by the smooth muscle cells of the stromal compartment of the gland. The mitogenic signals are initiated by the association of the growth factor with the external domain of receptors on the cell membrane. Through a tyrosine-specific protein kinase (TK) situated on the intracellular domain of the receptor, the binding of the peptide triggers a cascade of intracellular signaling events (Fig. 3.24) that ultimately lead to the activation of proto-oncogenes and gene transcription.125,126 Such signals could activate the c-myc, c-fos , and c-jun proto-oncogenes, all encoding proteins that are normally involved in normal growth-regulatory processes within the prostate gland and which are referred to as transcription factors (TFs). As well as encoding for transcription factors, proto-oncogenes would also encode for growthregulatory factors and their corresponding membrane receptor proteins, as well as for the many and various components of the signal transduction pathways. The current evidence therefore suggests that the androgenic effect on the prostate is at least partly mediated through the production of these mitogenic growth factors, with the target cells responding by expressing and activating a range of transcription factors that exercise a role in growth regulation. The Fos and Jun proteins, either as Fos/Jun heterodimers, or as Jun/Jun homodimers, are components of the AP-1 transcription factor that associates with the AP-1 recognition sequences on the genome (Fig. 3.25) characterized by the –TGACTCA– nucleotide
Figure 3.25 Diagrammatic representation of the concept of cross-talk between signaling pathways. DHT (D), dihydrotestosterone; AR, androgen receptor; TK, tyrosine kinase; GR, glucocorticoid receptor; RAR, retinoic acid receptor; Vit. D3R, vitamin D3 receptor. file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_47.html[09.07.2009 11:51:38]
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Page 48 sequence,127,128 with the interaction between the two proteins on the genome representing a specific interaction between the ‘leucine zipper’ structural domains of the proteins.129 The spatial disposition of the HREs or androgen response elements alongside AP-1 recognition sites in juxtaposition along the promoter region of an androgen responsive gene (Fig. 3.25) would therefore lead to functional interaction or synergism.130–132 Such interaction could be referred to as ‘cross-talk’ between signaling pathways. It has been reported that the binding of the ARs to particular androgen response elements is favored in the presence of NF-1 and NF-3 nucleotide consensus sequences.133 Also recognized is that the association of either the NF-1 transcription factor134 or the ER135 with the genome changes the spatial orientation of the DNA due to ‘bending’ of the DNA strands. It would seem that such interactions between the androgen receptor and the genome facilitate an easier accessibility for the transcription factors to their recognition sites.40 The concept of cross-talk is illustrated by experiments with estrogen responsive MCF-7 breast cancer cells in culture,96 to which EGF had been added (Fig. 3.26).
Figure 3.26 Interaction between steroid receptor protein and growth factor signaling pathways. EGF, epidermal growth factor; TKI, tyrosine-specific protein kinase inhibitor. Addition of a tyrosine-specific protein kinase inhibitor (ZM 252868, Zeneca, Alderly Edge, Macclesfield, UK) inhibited cell proliferation in a dose-dependent manner in the presence of EGF. The ZM 252868 specifically inhibits the mitogenic action of EGF and TGFα, the latter modulating cell proliferation through the EGF-R. Addition of the pure anti-estrogen ICI 182780, also in the presence of EGF, similarly suppressed cell proliferation in a dosedependent way, suggesting that the steroid receptor protein, either directly or indirectly, is necessary for the biological action of the growth factor. Little is known about the sensitivity of this type of interaction, nor of the concentrations of DHT-AR necessary to support growth factor signaling. Equally important is whether AR, in the absence of DHT, has the capacity constitutively to sustain basal levels of signaling. It would seem that although the prostate responds to a wide range of growth-regulatory factors,44,97 DHT appears to ‘fine tune’ these regulatory systems through the influence of the DHT-AR on the genome. Possibly the sensitivity of these systems is greater than hitherto had been appreciated, with probably an even greater sensitivity conferred on cancer cells.96 AR expression is maintained in most androgen-resistant cancers of the prostate,136 and it may be that under these circumstances the presence of AR confers a growth advantage, even in the presence of extremely low concentrations of androgen. The N-terminal (A/B) domain of the AR (Fig. 3.7) contains a ligand-independent transcription-activating file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_48.html[09.07.2009 11:51:38]
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function referred to as TAF-1. This domain also includes various homopolymeric stretches of amino acids, including 17 to 29 repeating glutamine residues and a 24-glycine stretch, and it has been suggested that it is the interaction of these homopolymeric stretches with other proteins such as the transcription factors that allows them to influence transcription,137,138 with the amino acids between 141 and 338 essential for TAF-1 transcription activation. The complexity of these interrelationships is further emphasized in Fig. 3.25, which illustrates how other proteins probably interact with AR, either as co-activators or co-repressors, to influence gene transcription.139,140 The potential interaction of the retinoic acid receptor, the glucocorticoid receptor, and the 1,25dihydroxyvitamin D3 (1,25-diOHvitD3) receptor that can interact with the Fos/Jun heterodimer complex to restrain transcription activity has been simply portrayed.141 It is clear that impairment of the growth-regulatory balance can lead to cellular hyperplasia with consequent genetic instability and subversion of the normal processes of growth restraint. Moreover, proto-oncogenes that
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Page 49 become dysfunctional through point mutations, deletions, amplification, or other changes that alter the structure or influence the expression of these growth regulatory genes can induce carcinogenesis. With the constant search for new therapeutic regimens, the potential of the tyrosine-specific tyrosine kinase inhibitors is obvious, and innovative drugs, essentially analogs of retinoic acid and 1,25diOHvitD3, may also have particular value. The place of glucocorticosteroids within the complex multihormonal environment of the prostate, with regard to growth control, may require re-assessment. The complexity of the stromal-epithelial interaction As stated, the interrelationship between stromal and epithelial compartments of the prostate gland would appear pivotal to growth regulation. The regional functional heterogeneity of the ductal system of the rat prostate,70–72 together with the different cell populations of the gland (Fig. 3.27), emphasizes the complexity of the system.44 In relation to the regional heterogeneity in the functional activity of the epithelial cells of the human ductal network, Fig. 3.28 diagrammatically represents certain functional differences between various regions of the rat prostatic ducts, with high epithelial proliferation reported in the distal segments and apoptosis in the proximal region. Animal studies45,46,142 indicate that the adult prostatic epithelium responds to inductive signals from the mesenchyme in a manner similar to that observed during fetal prostatic branching morphogenesis and development. Studies by Schalken et al.143 directed attention to the relative importance of this branching in the adult human prostate, using immunocytochemistry to reconstruct the morphological transition along the prostatic ductal structure. The glandular networks showed continuous transitions in morphology and immunoreactivity, with identification
Figure 3.27 The complex interrelationship between stromal and epithelial elements of the human prostate gland. TSH, thyroid-stimulating hormone; PSA, prostate-specific antigen; TGF, transforming growth factor; KGF, keratinocyte growth factor; FGF, fibroblast growth factor; IGF, insulin-like growth factors; IGF-BP, IGF-binding protein; DHT, dihydrotestosterone; T, testosterone; E2, estradiol.
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Page 50 of branch-like acini in the adult human prostate with unique phenotypic characteristics comparable with the developing prostate and the distal segments of the rat prostatic ducts (Fig. 3.28). These cells were characterized by a basal cell keratin phenotype, bcl-2 expression in all cells and a higher labeling index, seen from MIB-1 staining, when compared to mature glands. Intracellular E-cadherin expression was also prominent, as was an enhanced tenascin-C immunoreactivity, relating to active stromal-epithelial interaction. 144–148 Tenascin is a glycoprotein of the extracellular matrix which has been recognized as an essential factor for the modulation of the stromal-epithelial interactions which are reported in relation to wound healing of the skin, embryogenesis, and oncogenesis in other organs. It is of interest that Shalken et al. found that the expression of tenascin was enhanced in association with the newly formed epithelial components in the developing prostate and in the budding ductal tips.147,148 Tenascin expression was also found to be correlated with the grade of prostatic cancer, inversely relating to the expression of laminin and the relative disruption of the basement membrane. There was increasing expression of tenascin, from the levels associated with normal and BPH tissue through to those found in low- and high-grade PIN, in which the immunostaining was comparable with levels in ‘moderate grade’ tumors. These new and innovative studies from the laboratory of Schalken do much to support the concept of a regional heterogeneity of epithelial-stromal interaction and associated functional response within the human prostate, similar to that proposed by Chung Lee and Tenniswood70–72 for the ductal system of the rat. Growth regulatory factors implicated in the stromal-epithelial interaction The growth factors, together with the cells implicated in their production, which are intimately concerned in the interrelationship between stromal and epithelial elements of the human prostate gland, have been diagrammatically depicted earlier (Figs. 3,13, 3.15, and 3.27), with attention directed to KGF (FGF-7), FGF-2, and TGFβ.44
Figure 3.28 Comparison of prostatic branching morphogenesis between man and rat.
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Page 51 The current picture suggests a greater degree of complexity, even without consideration of the regional variability in function. The neuroendocrine cells are now seen to be playing a significant role in growthregulatory mechanisms and are possibly implicated in the focal pathogenesis of BPH. Their presence in association with cancer predicts an unfavorable prognosis.149 Although our knowledge concerning the function of these cells as well as their interrelationship with other cells is still limited, it is accepted that they represent a highly differentiated and specialized epithelial cell. Their keratin phenotype relates to that of the luminal epithelial cells. From a study of the ductal budding and branching patterns in the developing prostate, Timms et al.150 reemphasized the concept151 that the regional organization of the prostatic complex is determined by the regional heterogeneity of mesenchymal induction, with particular specific mesenchymal effects induced along a budding axis. This influence of stromal heterogeneity on growth and differentiation of the prostate gland, effects which are ‘imprinted’ on the gland during fetal life by the action of the various steroid hormones, is fundamentally important and relates to subsequent predisposition of various regions of the prostate to disease.150 This is discussed further in the following section that considers the role of estrogens on the prostate. Estrogens and the prostate Previous studies have centered on the ‘aging factor’ that relates to the pathogenesis of BPH and is seen primarily as an endocrine function. Essentially, the increasing prevalence of focal epithelial hyperplasia developing into nodular hyperplasia from the early twenties through to the late forties (Fig. 3.29) has been considered ‘androgen driven’ (Fig. 3.30). Estrogens, as well as androgens, have been seen to be implicated in the development of the adenoma associated with bladder outlet obstruction—a benign growth, which in most cases is predominantly composed of stromal elements, primarily muscle cells. This estrogenic stimulus is considered to be based on the consequence of a falling level of circulating testosterone sometime after the age of 50,44 relative to a sustained concentration of estrogen in the plasma (Fig. 3.31). Within the prostate, Krieg et al.152 have demonstrated a shift towards a higher estrogen/DHT ratio, with increasing age. With regard to the ‘imprinting role’ of estrogens on the fetal prostate in utero,150,153 Timms et al.153 reported that a physiological, 50% increase in the estradiol concentration within the male mouse fetus, produced from a maternal silastic implant, resulted in the development of an enlarged adult prostate gland, with a 6-fold increase in
Figure 3.29 The well-accepted growth profile of the human prostate and data showing the increased prevalence of microscopic BPH, epithelial hyperplasia, that is recognized in men as they age from the mid-twenties to later life.
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Figure 3.30 Diagrammatic illustration of the natural history of clinical BPH that causes bladder outlet obstruction. DHT, dihydrotestosterone.
Figure 3.31 The endocrine status of men at ‘mid-life’. The declining testicular function and associated fall in plasma testosterone (T) relative to the sustained level of circulating estrogen from the aromatase activity of adipose tissue increases the free estradiol (E2)/free testosterone ratio in the plasma. The free steroid, bound to neither plasma sex hormone-binding globulin (SHBG) nor albumin, is seen as the biologically active moiety in the plasma. 17 βOHSD, 17 beta hydroxy steroid dehydrogenase.
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Page 53 AR levels relative to controls. The implant increased the concentration of estradiol from 94 pg/ml to 146 pg/ml, the increase representing a difference of 0.1 pg/ml of free, biologically active estrogenic hormone, approximately 0.4 pmol/l. A 5-fold increase in the estradiol level of total serum, however, resulted in a smaller adult prostate gland. The results suggest that estrogens can modulate the action of androgens by enhancing the sensitivity of the prostate to androgen and, moreover, the effect is sustained throughout life, probably forming the basis of growth-regulatory dysfunction and disease in later years. It is of interest that the male mouse fetus, exposed to these physiological, small increases in estradiol levels, showed an immediate, significant increase in the number of prostate glands throughout the dorsal urogenital sinus, including the dorsocranial region. This region is considered homologous to the areas of the human prostate in which BPH originates.153 In relation to these studies, earlier investigations,154 directed to the estrogen levels in the plasma of pregnant black American women, indicated a 50% higher concentration of estradiol than in corresponding white women. The possible significance of these results in relation to the high prevalence of prostatic cancer in black American males is worthy of further investigation. It is certainly important to elucidate further the role of estradiol in the prostate gland, a plea voiced in many earlier venues.44,154,155 The recognition of the new estrogen receptor-β (ERβ) also emphasizes this need. Two reports156,157 have generated intense excitement in the field of endocrinology. The ER was cloned over a decade ago158 and it had been thought that only one receptor protein existed. These exciting reports describe a complementary DNA (cDNA) clone that encodes a new distinct, separate subtype of receptor, which is now referred to as ERβ. Of particular interest is that the human and rat ERß clones were recognized within cDNA libraries from the human testes and rat prostate. Interest now centers on the role of the ERβ. It is important to determine whether the ERβ has a similar biological role to that of the established estrogen receptor, now referred to as ERα. Their roles may be quite distinct, complementary, or antagonistic. Both have a high affinity for estradiol,159 although some estrogenic compounds show a preferential binding to ERβ. ERα predominates in the uterus, whereas ERβ is the major component in the prostate. Investigations with cDNA probes to ERβ identified cell-specific localization of ERβ in the secretory epithelial cells of the prostate,156 suggesting that ERβ may have a particular function in these cells. Previous reports44,65 have emphasized the exclusive localization of ER (ERα) in the stromal elements of the human prostate, with a predominance in the smooth muscle cells. The ERβ and ERα have very similar sequences of amino acids in the estrogen-binding domain of the protein, as well as in the DNA-binding domains, suggesting that they would associate with the same hormoneresponse elements on the genome. The N-terminal A/B regions and TAF-1 activation functions are, however, different, so that the cross-talk, or synergistic, functional interaction between the ERs and other cell-specific coactivators and -repressors in juxtaposition on the genome (Fig. 3.32) could be different for the ERβ relative to ERα within the prostate gland.160–164 Nucleotide recognition sequences may specifically interact with an ERα/ERβ heterodimer, for example, and it is now necessary to elucidate the molecular events associated with the role of ERβ in the prostate. The discovery of this new receptor for estrogens in the prostate gland will revitalize interest in the role of estrogens within the gland and their influence on growthregulatory processes. There will be renewed interest in the mechanism of action of the estrogens in general, but in particular, in relation to the new and novel ERß. There are many known biological roles for estradiol in nonreproductive systems, in particular on vascular tissue165 and bone. Some of the effects of estrogen on the vasculature relate to the production of nitric oxide, implicated in the proliferation of smooth muscle cells and also of prostacyclin and endothelin-1, factors concerned with the patency of the blood vessels. Within this context, the report from the third international consultation44 notes the presence of a specific plasma-membrane-located receptor for an estradiolZSHBG complex, that was found in the stromal elements of the human prostate. The estradiol-SHBG complex can induce intracellular signaling by promoting an 8-fold elevation in cAMP levels (Fig. 3.10). Nitric oxide (NO), a free radical associated with injury to tissue when reacting with the free radical superoxide, is now recognized as an important physiological regulator of certain endocrine systems. Nitric oxide is synonymous with endothelium-derived relaxing factor,166 which causes arterial vasodilatation.167 This nitrinergic system is assuming greater significance as studies develop. NOsynthase activation (Fig. 3.33) is concerned in LH-RH release from the hypothalamus168 and is recognized as a mediator of smooth muscle relaxation,169 and the neural NO-synthase is implicated in penile erection.170 Estradiol is believed to influence the L-arginine-NO-cGMP axis (Fig. 3.33) in
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Figure 3.32 Potential interrelationship between the estrogen-binding domain of the receptor proteins and the genome. E, estradiol; ER, estrogen receptor; KGF, keratinocyte growth factor. the promotion of parturition. Some consideration of the role of estrogens in relation to smooth muscle contractions within the prostate and in the maintenance of urinary flow will be of interest. NO generation may be involved in innervation.171 Studies with the rat insulinoma RINm5F cell line172 suggest that the induction of the NO-synthase may exercise a particular influence on the processes of apoptosis. The role of estrogens in relation to apoptosis in the prostate gland has not, as yet, been precisely determined, but recent important investigations by Kyprianou et al.173 indicate that the α1-adrenoceptor blocker doxazosin increased the apoptopic indices in both stromal muscle cells (15%) and epithelial cells (6%) of the prostates of men treated for BPH. The effect on the muscle cells was sustained for 12 months. The doxazosin was reported to relieve the symptoms of BPH in association with the induced smooth muscle cell apoptosis, together with stromal degeneration and diminished α-smooth muscle actin expression, molecular changes that appear to underlie the therapeutic response to α1-blockade. It has been suggested174 that the reaction between NO and superoxide that gives rise to the toxic peroxy nitrite (Fig. 3.33) may also be part of the natural process of apoptosis, by which phagocytes engulf and destroy foreign proteins, with ‘apoptopic genes’ encoding free radical scavengers.175,176 Anti-estrogenic therapeutic options related to the management of BPH In earlier reports,6,7,44 discussion has been directed to the potential benefits of anti-estrogen therapy for the management of the patient with clinical BPH. The use of the anti-estrogen tamoxifen suggested that the treatment caused stromal hyperplasia because of the estrogen agonistic properties of the drug, although dosage may not have been appropriate for the male. The use of an aromatase inhibitor alone was reported to be ineffective,177 although it could be thought that effective treatment should be directed to the withdrawal of both estrogens and androgens. A new and innovative approach, which may help to provide a greater understanding of the effect of decreasing the concentration of estrogens in the plasma of men with
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Figure 3.33 The concept of nitric oxide as a ‘second messenger’, whereby steroid hormones are implicated in its effect on muscle contractility and possibly in apoptosis. BPH, is the use of the compound mepartricin (SPA: Societa Prodotti Antibiotici SpA, Milan). Mepartricin, marketed under the trade name Ipertrofan, is a semisynthetic derivative of a polyene antibiotic isolated from a Streptomyces aureofaciens culture, existing as a mixture of two similar heptaenes (Fig. 3.34). In the doses used clinically, mepartricin is not systemically absorbed after oral administration and is well tolerated. Essentially, mepartricin irreversibly binds within the intestine, with the various estrogenic steroids, thereby interfering with the enterohepatic system that leads to the reabsorption of steroids from the gut (Fig. 3.35). In a manner similar to that pertaining to vegetarians on a high-fiber diet, there is an increased excretion of fecal estrogens as mepartricin-steroid complexes. The consequence of taking mepartricin, therefore, is a decrease in the concentration of estrogens in plasma, through the interruption of the enterohepatic recirculation of estrogens. The increased excretion of fecal estrogens and the consequent decline in plasma levels has been demonstrated in experimental animals after administration of mepartricin.178,179 In a controlled study of patients with BPH, treated with mepartricin for 30 days, a significant decrease in the concentrations of estradiol, estrone, and estriol has been reported.180,181 Short-term, double-blind, and openlabel studies have shown the clinical efficacy of mepartricin. A dose of 40 mg mepartricin daily, in placebocontrolled, double-blind clinical studies of up to 180 days,181 produced significant symptomatic improvement in patients with BPH, improving urinary flow rate and residual urine volume. Following the guidelines recommended by the International Consultation on BPH,182 mepartricin-treated patients were reported to experience a significant 39% decline in the International Prostate Symptom Score (I-PSS) after 6 months’ treatment. This simple and apparently effective form of therapy, that has no side-effects and none of the possible difficulties that could be associated with the more intrusive treatment involving anti-estrogenic drugs, may well help to increase our understanding of the role of estrogens in the prostate and, moreover, possibly in association with
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Figure 3.34 The structure of mepartricin.
Figure 3.35 Some steroid metabolic changes involved in the enterohepatic circulation, with interchange of sulfate (S) and glucuronide (G) residues on the estrogens. E1, estrone; E2, estradiol; E3 estriol. anti-androgen therapy, offer a new, innovative approach to the management of BPH. BPH: hereditary predisposition The concepts discussed in this chapter clearly emphasize the complexity of prostatic growth control. The etiology of BPH is undoubtedly multifactorial and, although the two principal risk factors relate to aging and functional testes, evidence continues to accumulate to suggest that a familial history of BPH may also constitute a risk factor. The evidence indicates a predisposing genetic element in patients with early onset BPH and that ‘DNA abnormalities’ may contribute to the pathogenesis of the disease. DNA fingerprinting has demonstrated a high frequency of genomic alterations in prostate tissue from patients with
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Page 57 BPH relative to normal human tissue.183,184 Molecular abnormalities in the DNA sequences relating to the growth suppressor gene p53 have been identified in approximately 40% of BPH tissue when analyzed at this genetic locus and abnormal nucleotide methylation patterns are also present185. BPH can be genetically induced in transgenic mice by activation of the int-2 gene.186,187 Sanda et al.,188 in a case-control study of familial clustering of clinical BPH, identified a family history of BPH as a major risk factor for the development of the disease that required surgical intervention at an early age. Of interest was that the male relatives of men who developed this early onset BPH had a 66% cumulative lifetime risk of prostatectomy for BPH compared to a 17% risk among the control group. The data provided evidence of a dominant Mendelian transmission of a genetic allele and are supported by observations of a higher concordance of BPH among monozygotic twins when compared to their dizygotic counterparts.189 In a corresponding study,190 it was reported that familial BPH was characterized by a larger prostate size, but normal concentrations of serum testosterone and a normal response to 5α-reductase inhibitors. The authors suggest that the hereditary factors relating to BPH may influence the prostate through androgen-independent processes. In relation to this concept, Doehring et al.191 demonstrated that these larger prostates of young men with ‘hereditary BPH’ are associated with higher stromal/epithelial ratios. Diet and prostate disease: the concept of prevention The relationship of diet to prostate disease has been the subject of a recent major review.192,193 From the marked differences in the incidence of both prostate and breast cancer between the East and the West (Fig. 3.36), it was not difficult to direct attention to fat and animal products, which can provide up to 40% of the total caloric intake in some North American people, as possible causative factors. Recently, however, an alternative concept has emerged to suggest that constituents of the Asian diet may restrain the processes of carcinogenesis.193 Studies of people migrating from Japan and China, through Hawaii, to mainland USA indicate that the migrants, in one or two generations, show a mortality rate for prostate cancer that comes close to that of the indigenous American people, thereby highlighting a possible influence of dietary factors.194,195 Interest now centers on isoflavonoids, flavonoids, and lignans, products of vegetables, fruit, whole grains, and soya, that are metabolized by the gut microflora to give rise to compounds such as enterolactone, daidzein, and
Figure 3.36 Incidence of breast and prostate cancer in countries from the East and West.
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Page 58 genistein (Fig. 3.37), weak plant estrogens, referred to generally as the phytoestrogens. As weak estrogens, such compounds could act as ‘natural tamoxifen-like’ factors that could, like tamoxifen, which is also a weak estrogen agonist, restrain the early processes associated with breast carcinogenesis by their antagonistic anti-estrogenic effect. Estrogenic substances in plants The presence in plants of nonsteroidal substances with estrogenic activity has been recognized for some time and many hundreds of plants manifest some degree of estrogenic activity.196,197 Soya bean and red clover are members of the leguminosae family and are a major source of isoflavonoids.197–199 Soya is consumed daily in large amounts in a number of forms in China and Japan and in Asia generally. Many foods of plant origin contain varying amounts of isoflavonoids, flavonoids, and lignans (Fig. 3.38). Some of these polyphenolic phytoestrogens possess weak estrogenic activity and therefore the potential for exerting an influence on hormone-dependent cancers such as those of the breast and prostate.200 Soya beans contain the glycoside conjugates of the isoflavonoids genistein and daidzein, which can be metabolized by gut bacteria to the aglycones. Genistein can be further metabolized to the nonestrogenic p -ethylphenol and daidzein is converted to the estrogenic isoflavan, equol. The aglycones and their metabolites are then absorbed and appear in blood and urine, primarily as glucuronide conjugates and also as sulfates.200 Daidzein and genistein were isolated from soya beans more than 70 years ago201 and 100 g fat-free soya beans may yield up to 300 mg genistein.202 Generally, the presence of isoflavonoids in plants is limited to legumes, although they have recently been identified in beer and bourbon203,204 and may be more widely distributed than was previously thought. Lignans are another group of polyphenolic plant compounds.197,205 The plant precursors, matairesinol and secoisolariciresinol, are metabolized after ingestion by intestinal microflora to give rise to the weakly estrogenic enterolactone and enterodiol, respectively. The lignans are absorbed from the gut to appear in blood and other body fluids.200 The lignans are widely distributed in nature and precursors are found in many cereals, grains, fruits, and vegetables, but the richest source is linseed (flaxseed) and other oilseeds such as sesame.206 Isoflavonoids and lignans are normal constituents of body fluids and have been identified in most animal200 and human body fluids by gas chromatography-mass spectrometry (GC-MS).207 They are present in urine,208,209 plasma,210 saliva,211 and semen.212 Analysis of expressed prostatic fluid found that enterolactone and equol were constituents,211 suggesting that dietary estrogens can accumulate in the prostate.
Figure 3.37 The structure of certain phytoestrogens.
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Page 59 The levels of isoflavonoids are high in the urine and plasma (Fig. 3.39) of the Japanese and Chinese,207,213,214 whose traditional foodstuffs contain large amounts of soya in the form of bean curd (tofu), soya bean milk, miso, and tempeh. The concentration of lignans is high in the urine of vegetarians,209 whose diet contains whole-grain cereals, vegetables, and fruits. In Western subjects fed 40 g soya daily, the urinary excretion of equol was found to increase 1000-fold above control levels.199,215 The concentrations of flavonoids in plasma and urine of different populations have yet to be determined and present an obvious program for future research. However, as tea, fruit, and vegetables are the principal sources of flavonoids, it is probable that Asians, with their high consumption of tea, and vegetarians have significant circulating levels of these compounds. Whether such phytoestrogens could restrain prostate carcinogenesis through their influence on the physiological actions of estrogens in the growth-regulatory events of the prostate is controversial.216 These compounds, however, exercise other influences on cell biology. The following are some of the reported properties of the phytoestrogens:
Figure 3.38 Sources of phytoestrogens.
Figure 3.39 Comparative mean concentrations of isoflavonoids, genistein, and daidzein in normal British and Japanese subjects.
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Page 60 • Inhibition of 5α-reductase activity;217,218 • Inhibition of aromatase activity;219,220 • Inhibition of tyrosine-specific protein kinases;221,222 • Inhibition of angiogenesis;223,224 • Influence on free radicals as antioxidants;225,226 • Influence on the topoisomerase enzymes;227–230 • Inhibition of tumorigenesis in experimental animals.231–234 The imprinting influence of estrogens in utero on the male fetal prostate, biological actions whose consequences are often manifest later in life, may also be influenced by such dietary factors. These steroid-imprinting effects would seem of particular importance in determining the subsequent growth patterns of the gland as it develops and their influence is sustained throughout life. Acknowledgment The authors are grateful to Mr David Griffiths, CompGraphics, Cardiff, who owns the copyright for the illustrations in this chapter. The authors also acknowledge the work and support of the committee concerned with the regulation of prostatic growth, which was part of the recent International Consultation on BPH, held in Paris in 2000. Some of the conclusions and illustrations in the report of the committee are included in this chapter. References 1. Griffiths K, Cockett A T K, Coffey D S et al. Regulation of prostate growth. In: Denis L J, Cockett A T K, Chatelein C et al. (eds). The fourth international consultation on BPH. Paris: SCI Press, 1998:85–128 2. Garraway W M, Collins G N, Lee R J. High prevalence of benign prostatic hypertrophy in the community. Lancet 1991; 338:469–471 3. Barry M J, Beckley S, Boyle P et al. Importance of understanding the epidemiology and natural history of BPH. In: Cockett A T K, Aso Y, Chatelain C et al. (eds). The first international consultation on benign prostatic hyperplasia (BPH). Paris: SCI Press, 1991:13–21 4. Glynne R J, Campion E W, Bouchard G R, Silbert J E. The development of benign prostatic hyperplasia among volunteers in the normative aging study. Am J Epidemiol 1985; 121:78–90 5. Lytton B, Emery J M, Harvard B M. The incidence of benign prostatic obstruction. J Urol 1968; 99:639–645 6. Griffiths K, Akaza H, Eaton C L et al. Hormones, growth factors and benign prostatic hyperplasia (BPH). In: Cockett A T K, Aso Y, Chatelain C et al. (eds). The first consultation on benign prostatic hyperplasia (BPH). Paris: SCI Press, 1991:25–49 7. Griffiths K, Akaza H, Eaton C L et al Regulation of prostatic growth. In: Cockett A T K, Khoury S, Aso Y et al. (eds). The second international consultation on benign prostatic hyperplasia (BPH). Paris: SCI Press, 1993:49–75 8. Riad-Fahmy D, Read G F, Walker R F, Griffiths K. Steroids in saliva for assessing endocrine function. Endocr Rev 1982; 3:367–395 9. Vermeulen A, Deslypere J P, Meirleir K. A new look at the andropause: altered function of the gonadotrophs. J Steroid Biochem 1989; 32:163–165 10. Schroeder F H, Westerhof M, Bosch R J L H, Kurth K H. Benign prostatic hyperplasia treated by castration or the LH-RH analogue buserelin: a report on six cases. Eur Urol 1986; 12:318–321 11. Baird D T, Uno A, Melby J C. Adrenal secretion of androgens and oestrogens. J Endocrinol 1969; 45:135–136 12. Lipsett M B. Steroid secretion by the human testis. In: Rosemberg E, Paulsen C A (eds). The human testis. New York: Plenum Press, 1970:407–421 13. Santen R J, Bardin C W. Episodic luteinizing hormone secretion in man. Pulse analysis, clinical interpretation, physiological mechanisms. J Clin Invest 1973; 52: 2617–2628 14. Longcope C, Widrich W, Sawin C T. The secretion of estrone and estradiol-17ß by human testis. Steroids 1972; 20:439–448 15. Baird D T, Galbraith A, Fraser I S, Newsam J E. The concentration of oestrone and oestradiol-17α in spermatic venous blood in man. J Endocrinol 1973; 57:285–288 16. McDonald P C. Origin of estrogen in man. In: Grayhack J T, Wilson J D, Schebenske M J (eds). Benign prostatic hyperplasia, NIAMDD Workshop Proceedings. DHEW Publication No (NIH) 76–1113. Bethesda: NIH, 1976: 191–193 17. Vermeulen A, Rubens R, Verdonck L. Testosterone secretion and metabolism in male senescence. J Clin Endocrinol Metab 1972; 34:730–735 18. Vermeulen A, Van Camp A, Mattelaer J, De Sy W. Hormonal factors related to abnormal growth of file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_60.html[09.07.2009 11:51:44]
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the prostate. In: Coffey D S, Isaacs J T (eds). Prostate cancer. UICC Technical Report Series, Vol 48. Geneva: UICC, 1979:81–92 19. Vermeulen A. Testicular hormone secretion and aging in males. In: Grayhack J T, Wilson J D, Scherbenske M J (eds). Benign prostatic hyperplasia. NIAMDD Workshop Proceedings. NIH Publication No (NIH) 76–1113. Bethesda: NIH, 1976:177–182 20. Rubens R, Dhont M, Vermeulen A. Further studies on Leydig cell function in old age. J Clin Endocrinol Metab 1974; 39:40–45
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Page 61 21. Rosner W. The functions of corticosteroid-binding globulin and sex hormone-binding globulin: recent advances. Endocr Rev 1990; 11:80–91 22. Loukovaara M, Carson M, Adlercreutz H. Regulation of production and secretion of sex hormonebinding globulin in HepG2 cell cultures by hormones and growth factors. J Clin Endocrinol Metab 1995; 80:160–164 23. Mousavi Y, Adlercreutz H. Genistein is an effective stimulator of sex hormone-binding globulin production in hepatocarcinoma human liver cancer cells in culture. Steroids 1993; 58:301–304 24. Bruchovsky N, Wilson J D. The intranuclear binding of testosterone and 5α-androstan-17ß-ol-3-one by rat prostate. J Biol Chem 1968; 243:5953–5960 25. Bruchovsky N, Wilson J D. The conversion of testosterone to 5α-androstan-17ß-ol-3-one by rat prostate in vivo and in vitro. J Biol Chem 1968; 243:2012–2021 26. Harper M E, Pike A, Peeling W B, Griffiths K. Steroids of adrenal origin metabolized by human prostatic tissue both in vivo and in vitro. J Endocrinol 1974; 60:117–125 27. Harper M E, Peeling W B, Griffiths K. Adrenal androgens and the prostate. In: Motta M, Serio M (eds). Hormonal therapy of prostatic disease: basic and clinical aspects. Netherlands: Medicom Europe, 1988:81–104 28. Labrie F, Dupont A, Belanger A. New approach in the treatment of prostatic cancer: complete instead of partial withdrawal of androgens. Prostate 1983; 4:579–594 29. Labrie F, Dupont A, Belanger A. Spectacular response to combined antihormonal treatment in advanced prostate cancer. In: Labrie F, Prouix L (eds). Endocrinology, international congress series. Amsterdam: Excerpta Medica, 1984:450–453 30. Denis L J. Controversies in the management of localised and metastatic prostatic cancer. Eur J Cancer 1991; 27: 333–341 31. Muntzing J. The androgenic action of adrenal implants in the ventral prostate of adult, castrated and oestrogentreated rats. Acta Pharmacol Toxicol (Kbh) 1971; 30: 203–207 32. Nicholson R I, Davies P, Griffiths K. Interaction of androgens with oestradiol-17ß receptor proteins in DMBA-induced mammary tumours—a possible oncolytic mechanism. Eur J Cancer 1978; 14:439–445 33. Griffiths K, Davies P, Harper M E et al. The etiology and endocrinology of prostatic cancer. In: Rose D (ed). Endocrinology of cancer. Vol 2. Boca Raton: CRC Press, 1979:1–55 34. Griffiths K, Davies P, Eaton CL et al. Cancer of the prostate: endocrine factors. In: Clarke JR (ed). Oxford reviews of reproductive biology. Vol 9. Oxford: Oxford University Press, 1987:192–259 35. MacDonald P C, Grodin J M, Siiteri P K. Dynamics of androgen and estrogen secretion. In: Baird D T, Strong J A (eds). Control of gonadal steroid secretion. Baltimore: Williams & Wilkins 1972:157–167 36. Kley H K, Nieschlag E, Bidlingmaier F, Kruskemper H L. Possible age-dependent influence of estrogens on the binding of testosterone in plasma of adult men. Horm Metab Res 1974; 6:213–221 37. Baker H W G, Burger H G, De Kretser D M et al. Changes in the pituitary-testicular system with age. Clin Endocrinol (Oxf) 1976; 5:349 38. Hryb D J, Kahn M S, Romas N A, Rosner W. Solubilization and partial characterization of the sex hormone-binding globulin receptor from human prostate. J Biol Chem 1989; 264:5378–5383 39. Bruchovsky N, Lesser B, VanDoorn E, Craven S. Hormonal effects on cell proliferation in rat prostate. Vit Horm 1975; 33:61–102 40. Truss M, Beato M. Steroid hormone receptors: interaction with deoxyribonucleic acid and transcription factors. Endocr Rev 1993; 14:459–479 41. Wiseman H, Duffy R. New advances in the understanding of the role of steroids and steroid receptors. Biochem Soc Trans 2001; 29:205–209 42. Imperato-McGinley J, Guerro L, Gautier T, Peterson R E. Steroid 5α-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science 1974; 186: 1213–1215 43. Lee C, Kozlowski J M, Grayhack J T. Intrinsic and extrinsic factors controlling benign prostatic growth. Prostate 1997; 31:131–138 44. Griffiths K, Coffey D, Cockett A T K et al. The regulation of prostatic growth. In: Cockett ATK, Khoury S, Aso Y et al. (eds). The third international consultation on benign prostatic hyperplasia. Paris: SCI, 1996:73–115 45. Cunha G R, Chung L W K, Shannon J M et al. Hormoneinduced morphogenesis and growth: role of mesenchymal-epithelial interactions. Rec Prog Horm Res 1983; 39: 559–595 46. Chung L W K, Cunha G R. Stromal-epithelial interactions: II Regulation of prostatic growth by embryonic urogenital sinus mesenchyme. Prostate 1983; 4:503–511 47. Franks L M, Riddle P N, Carbonell A W, Gey G O. A comparative study of the ultrastructure and lack file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_61.html[09.07.2009 11:51:45]
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of growth capacity of adult human prostate epithelium mechanically separated from its stroma. J Pathol 1970; 100:113–119 48. Yan G, Fukabori Y, Nikoloropolous S et al. Heparin-binding keratinocyte growth factor is a candidate stromal to epithelial cell andromedin. Mol Endocrinol 1992; 6: 2123–2128 49. Peehl D M, Stamey T A, Rubin J S. Fibroblast growth factors can replace epidermal growth factor for clonal
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Page 62 proliferation of human prostatic epithelial cells. J Urol 1991; 145:475 50. Sugimura Y, Cunha G R, Haywood S et al. Keratinocyte growth factor (KGF) is a mediator of testosterone induced prostatic development. J Urol 1994; 151:381 51. Alarid E T, Rubin J S, Young P et al. Keratinocyte growth factor functions in epithelial induction during seminal vesicle development. Proc Natl Acad Sci USA 1994; 91: 1074–1078 52. Culig Z, Hobixch A, Cronauer M V et al. Androgen receptor activation in prostatic tumour cell lines by insulin-like growth factor I, keratinocyte growth factor and epidermal growth factor. Cancer Res 1994; 54: 5474–5478 53. Guo L, Degenstein L, Fuchs E. Keratinocyte growth factor is required for hair development but not for wound healing. Genes Dev 1996; 10:165–175 54. Miki T, Bottaro D P, Fleming T P et al. Determination of ligand-binding specificity by alternate splicing: two distinct growth factor receptors encoded by a single gene. Proc Natl Acad Sci USA 1992; 89:246–250 55. Story M T, Livingstone B, Baeten L et al. Cultured human prostate-derived fibroblasts produce a factor that stimulates their growth with properties indistinguishable from basic fibroblast growth factor. Prostate 1989; 15:355–365 56. Mansson P E, Adams P, Kan M, McKeehan W L. Heparinbinding growth factor gene expression and receptor characteristics in normal rat prostate and two transplantable rat prostate tumors. Cancer Res 1989; 49:2485–2494 57. Sherwood E R, Fong C J, Lee C, Kozlowski J M. Basic fibroblast growth factor: a potential mediator of stromal growth in the human prostate. Endocrinology 1992; 130: 2955–2963 58. Lawson R K. Etiology of benign prostatic hyperplasia. In: Lepor H, Lawson RK (eds). Prostate diseases. Philadelphia: Saunders, 1993:89–95 59. Leung H Y, Dickson C, Robson C N, Neal D E. Overexpression of fibroblast growth factor-8 in human prostate cancer. Oncogene 1996; 12:1833–1835 60. MacArthur C A, Lawshe A, Shankar D B et al. FGF-8 isoforms differ in NIH3t3 cell transforming potential. Cell Growth Diff 1995; 6:817–825 61. Schmitt J F, Hearn M T, Risbridger G P. Expression of fibroblast growth factor-8 in adult rat tissues and human prostate carcinoma cells. J Steroid Biochem Mol Biol 1996; 57:173–178 62. Yan G, Fukabori Y, McBride G et al. Exon switching and activation of stromal and embryonic fibroblast growth factor (FGF)-FGF receptor genes in prostate epithelial cells accompany stromal independence and malignancy. Mol Cell Biol 1993; 13:4513–4522 63. MacArthur C A, Lawshe A, Xu J et al. FGF-8 isoforms activate receptor splice variants that are expressed in mesenchymal regions of mouse development. Development 1995; 121:3603–3613 64. Ittman M, Mansukhani A. Expression of fibroblast growth factors (FGFs) and FGF receptors in human prostate. J Urol 1997; 157:351–356 65. Krieg M, Bartsch W, Thomsen M, Voigt K D. Androgens and estrogens: their interaction with stroma and epithelium of human benign prostatic hyperplasia and normal prostate. J Steroid Biochem 1983; 19:155–161 66. Habenicht U F, El Etreby M F. Selective inhibition of androstenedione-induced prostate growth in intact beagle dogs by a combined treatment with the antiandrogen cyproterone acetate and the aromatase inhibitor 1-methyl-androsta-1, 4-diene-3, 17-dione. Prostate 1989; 14: 309–322 67. Rohr H P, Bartsch G. Human benign prostatic hyperplasia: a stromal disease? New perspectives by quantitative morphology. Urology 1980; 16:625–633 68. McNeal J E. Normal histology of the prostate. Am J Surg Pathol 1988; 12:629–633 69. Lee C, Sensibar J A, Dudek S M et al. Prostatic ductal system in rats: regional variation in morphological and functional activities. Biol Reprod 1990; 43:1079–1086 70. Sensibar J A, Griswold M D, Sylvester S R. Prostatic ductal system in rats: regional variation in localisation of an androgen-repressed gene product, sulfated glycoprotein-2. Endocrinology 1991; 128:2091–2102 71. Wong P, Pineault J, Lakins J N et al. Genomic organisation and expression of the rat TRPM-2 (clusterin) gene, a gene implicated in apoptosis. J Biol Chem 1993; 268: 5021–5031 72. Rouleau M, Leger J, Tenniswood M P. Ductal heterogeneity of cytokeratins, gene expression and cell death in the rat ventral prostate. Mol Endocrinol 1990; 4:2003–2013 73. Kyprianou N, Isaacs J T. Expression of transforming growth factors in the rat ventral prostate during castration-induced programmed cell death. Mol Endocrinol 1989; 3:1515–1522 file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_62.html[09.07.2009 11:51:45]
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74. Isaacs J T. Antagonistic effect of androgen on prostatic cell death. Prostate 1984; 5:545–557 75. Ichihara I, Kallio M, Pelliniemi L J. Light and electron microscopy of the ducts and their sub-epithelial tissue in the rat ventral prostate. Cell Tissue Res 1978; 192: 381–390 76. Lee C, Kozlowski J M, Grayhack J T. Etiology of benign prostatic hyperplasia. Urol Clin North Am 1995; 22: 237–246 77. Nemeth J A, Lee C. The prostatic ductal system in rats: regional variation in stromal organisation. Prostate 1996; 28:124–128
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Page 63 78. Cooke P S, Young P, Cunha G R. Androgen receptor expression in developing male reproductive organs. Endocrinology 1991; 128:2867–2873 79. Cooke P S, Young P, Hess R A, Cunha G R. Estrogen receptor expression in developing epididymis, efferent ductules and other male reproductive tissues. Endocrinology 1991; 128:2874–2879 80. Toney T W, Danzo BJ. Developmental changes in and hormonal regulation of estrogen and androgen receptors present in the rabbit epididymis. Biol Reprod 1988; 39: 818–828 81. Toney T W, Danzo B J. Androgen and estrogen effects on protein synthesis by the adult rabbit epididymis. Endocrinology 1989; 125:243–249 82. Bruengger A, Mariotti A, Rohr H P et al. Androgen and estrogen effects on guinea pig seminal vesicle muscle: a combined serological and biochemical study. Prostate 1986; 9:303–310 83. Steiner M S. Role of peptide growth factors in the prostate: a review. Urology 1993; 42:99–110 84. Di Sant Agnese P. Neuroendocrine differeniation in carcinoma of the prostate. Diagnostic, prognostic and therapeutic implications. Cancer 1992; 70:254–268 85. Larsson L I. On the possible existence of multiple endocrine, paracrine and neuroendocrine messengers in secretory cell systems. Invest Cell Pathol 1980; 3:73–85 86. Grube D. The endocrine cells of the digestive system: amines, peptides and modes of action. Anat Embryol 1986; 175:151–162 87. Cockett A T K, Di Sant Agnese P A, Gopinath P et al. Relationship of neuroendocrine cells of prostate and serotonin to benign prostatic hyperplasia. Urology 1993; 42: 512–519 88. Bologna M, Festuccia C, Muzi P et al. Bombesin stimulates growth of human prostatic cancer cells in vitro. Cancer 1989; 63:1714–1720 89. Aprikian A, Han K, Chevalier S et al. Bombesin specifically induces intracellular calcium mobilisation via gastrin-releasing peptide receptors in human prostate cancer cells. J Mol Endocrinol 1996; 16:297– 306 90. Wasilenko A, Cooper J, Palad A et al. Calcium signalling in prostate cancer cells: evidence for multiple receptors and enhanced sensitivity to bombesin/GRP Prostate 1997; 30:167–173 91. Han K, Viallet J, Chevalier S et al. Characterisation of intracellular calcium mobilisation by bombesinrelated neuropeptides in PC-3 human prostate cancer cells. Prostate 1997; 31:53–60 92. Ritchie C, Thomas K, Andrews L et al. Effects of the calciotrophic peptides calcitonin and parathyroid hormone on prostate cancer growth and chemotaxis. Prostate 1997; 30:183–187 93. Iwamura M, Wu G, Abrahamsson P A et al. Parathyroid hormone-related protein: a potential autocrine growth regulator in human prostate cancer cell lines. Urology 1994; 43:675–679 94. Abdul M, Anezinis P, Logothetis C, Hoosein N. Growth inhibition of human prostatic carcinoma cell lines by serotonin antagonists. Anticancer Res 1994; 14:1215–1220 95. Harper M E, Glynne-Jones E, Goddard L et al. Vascular endothelial growth factor (VEGF) expression in prostatic tumours and its relationship to neuroendocrine cells. Br J Cancer 1996; 74:910–916 96. Griffiths K, Morton M S, Nicholson R I. Androgens, androgen receptors, antiandrogens and the treatment of prostate cancer. Eur Urol 1997; 32 (Suppl 3): 24–40 97. Isaacs J T, Cussenot O, Jankevicius F et al. Growth regulation of normal and malignant prostatic cells. In: Murphy G, Denis L, Chatelain C et al. (eds). First international consultation on prostate cancer. Paris: SCI, 1996:31–81 98. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 1990; 82:4–6 99. Folkman J, Klagsbrun M. Angiogenic factors. Science 1987; 235:442–447 100. Weidner N, Carroll P R, Flax J et al. Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 1993; 143:401–409 101. Bang Y, Pirnia F, Fang W et al. Terminal neuroendocrine differentiation of human prostate carcinoma cells in response to increased intracellular cyclic AMP Proc Natl Acad Sci USA 1994; 91:5330– 5334 102. Segal N, Cohen R, Huffejee Z, Savage N. Bcl-2 protooncogene expression in prostate cancer and its relationship to the prostatic neuroendocrine cell. Arch Pathol Lab Med 1994; 118:616–618 103. Seuwen K, Poiyssegur J. Serotonin as a growth factor. Biochem Pharmacol 1990; 39:985–990 104. Kinghorn E M, Bate A S, Higgins S J. Growth of rat seminal vesicle epithelial cells in culture: neurotransmitters are required for androgen-regulated synthesis of tissuespecific secretory proteins. Endocrinology 1987; 121: 1678–1688 105. Tutton B J, Barkla D H. Biogenic amines as regulators of the proliferative activity of normal and neoplastic intestinal epithelial cells. Anticancer Res 1987; 7:1–12 file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_63.html[09.07.2009 11:51:46]
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106. Nemecek G M, Coughlin S R, Handley D A, Moskowitz M A. Stimulation of aortic smooth muscle cell mitogenesis by serotonin. Proc Natl Acad Sci USA 1986; 83: 674–678 107. Seuwen K, Magnaldo I, Pouyssegue J. Serotonin stimulates DNA synthesis in fibroblasts acting through 5-HT1B receptors coupled to G-protein. Nature 1988; 335: 254–256
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Page 64 108. Cockett A T K, Di Sant Agnese P A, Gopinath P et al. Relationship of neuroendocrine cells of prostate and serotonin to benign prostatic hyperplasia. Adult Urol 1993; 42:512–519 109. Power R F, Mani S K, Codina J et al. Dopaminergic and ligand-independent activation of steroid hormone receptors. Science 1991; 254:1636–1639 110. Verhagen A P M, Aalders T W, Ramaekers F C S et al. Differential expression of keratins in the basal and luminal compartments of rat prostate epithelium during degeneration and regeneration. Prostate 1988; 13:25–38 111. Isaacs J T, Coffey D S. Etiology and disease process of benign prostatic hyperplasia. Prostate 1989; 2 (Suppl 2): 33–50 112. Isaacs J T. Control of cell proliferation and cell death in the normal and neoplastic prostate: a stem cell model. In: Rodgers C H, Coffey D S, Cunha G R et al. (eds). Benign prostatic hyperplasia. Vol II, NIH Publication No. 87–2881. Bethesda: NIH, 1987:85–94 113. Bonkhoff H, Stein U, Remberger K. Multidirectional differentiation in the normal, hyperplastic, and neoplastic human prostate: simultaneous demonstration of cell-specific epithelial markers. Hum Pathol 1994; 25:42–46 114. Bonkhoff H, Remberger K. Differentiation pathways and histogenetic aspects of normal and abnormal prostatic growth: a stem cell model. Prostate 1996; 28:98–106 115. Denmeade S R, Lin S X, Isaacs J T. The role of programmed (apoptotic) cell death during the progression and therapy for prostate cancer. Prostate 1995; 28: 251–265 116. Colombel M, Symmans F, Gil S et al. Detection of the apoptosis-suppressing oncoprotein bcl-2 in hormone refractory human prostate cancers. Am J Pathol 1993; 143:390–400 117. Raffo A J, Perlman H, Chen M W et al. Overexpression of bcl-2 protects prostate cancer from apoptosis in vitro and confers resistance to androgen depletion in vivo. Cancer Res 1995; 55:4438–4445 118. McDonnell M L, Troncoso P, Brisbay S M et al. Expression of the proto-oncogene bcl-2 in prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res 1992; 52:6940–6944 119. Kim N W, Hruszkewyez A M. Telomerase activity modulation in the prevention of prostate cancer. Urology 2001; 57 (Suppl 1): 148–153 120. Sommerfeld H, Meeker A K, Piatyszek M A et al. Telomerase activity: a prevalent marker of malignant human prostate tissue. Cancer Res 1996; 56:218–222 121. Sommerfeld H, Meeker A K, Posadas E M, Coffey D S. Frontiers in prostate cancer: telomeres and chaos. Cancer 1995; 75:2027–2035 122. Robinson S I, Small D, Idzerda R et al. The association of transcriptionally active genes with the nuclear matrix of the chick oviduct. Nucl Acid Res 1983; 11:5113–5130 123. Nickerson J A, He D, Fey E G, Penman S. The nuclear matrix. In: Strauss P R, Wilson S H (eds). The eukaryotic nucleus: molecular biochemistry and macromolecular assemblies, Vol 2. Caldwell: Telford Press, 1990 124. Barrack E R, Coffey D S. The specific binding of oestrogens and androgens to the nuclear matrix of sex hormone responsive tissues. J Biol Chem 1980; 255:7265–7275 125. Aaronson S. Growth factors and cancer. Science 1991; 254:1146–1153 126. Weinberg R A. The molecular basis of oncogenes and tumor suppressor genes. Ann NY Acad Sci 1995; 758: 331–338 127. Curran T, Bravo R, Muller R. Transient induction of c-fos and c-myc is an intermediate consequence of growth factor stimulation. Cancer Surv 1985; 4:655–681 128. Jones N. Transcriptional regulation by dimerisation: two sides to an incestuous relationship. Cell 1990; 61:9–11 129. Landschultz W H, Johnson P F, McKnight S L. The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins. Science 1986; 240: 1759–1764 130. Diamond M I, Miner J N, Yoshinaga S K, Yamamoto K R. Transcription factor interactions: selections of positive and negative regulation from a single DNA element. Science 1990; 249:1266–1272 131. Schule R, Muller M, Kaltschmidt C, Rentawitz R. Many transcription factors interact synergistically with steroid receptors. Science 1988; 242:1418–1420 132. Shemshedini L, Knauthe R, Sassone-Corsi P et al. Cell specific inhibitory and stimulatory effects of fos and jun on transcription activation by nuclear receptors. EMBO J 1991; 10:3839–3849 133. Griffiths K, Davies P, Eaton C L et al. Endocrine factors in the initiation, diagnosis and treatment of prostate cancer. In: Voigt K D, Knabbe C (eds). Endocrine dependent tumors. New York: Raven Press, 1991:83–130 file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_64.html[09.07.2009 11:51:46]
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134. Sabbah M, Le Recousse S, Redeuilh G, Beaulieu E E. Estrogen receptor-induced binding of the xenopus vitellogenin A2 gene hormone response element. Biochem Biophys Res Commun 1992; 185:944–952 135. Nardulli A M, Shapiro D J. Binding of the estrogen receptor DNA-binding domain to the estrogen response element induces DNA binding. Mol Cell Biol 1992; 12: 2037–2042 136. Chodak G W, Krane D M, Puy L A et al. Nuclear localization of androgen receptor in heterogeneous samples of normal, hyperplastic and neoplastic human prostate. J Urol 1992; 147:798–803
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Page 65 137. Gerber H P, Seipel K, Georgiev O et al. Transcriptional activation modulated by homopolymeric glutamine and proline stretches. Science 1994; 263:808–811 138. Jenster G, van der Korput H A G M, Trapman J, Brinkmann A G. Identification of two transcriptional activation units in the N-terminal domain of the human androgen receptor. J Biol Chem 1995; 270:7341– 7346 139. Beato M, Herrlich P, Schutz G. Steroid hormone receptors: many actors in search of a plot. Cell 1995; 83: 851–857 140. Mangelsdorf D J, Evans R M. The RXR heterodimers and orphan receptors. Cell 1995; 83:841–850 141. Saatcioglu F, Claret F X, Karin M. Negative transcriptional regulation by nuclear receptors. Semin Cancer Biol 1994; 5:347–359 142. Sugimura Y, Cunha G R, Donjacour A A et al. Whole mount autoradiography study of DNA synthetic activity during postnatal development and androgen-induced regeneration in the mouse prostate. Biol Reprod 1986; 34: 985–995 143. Xue Y, Schalken J A, Miller G J et al. Immunohistochemical determination of in vivo distribution of branching patterns in human adult prostate. J Urol 1996; 155:332A 144. Lightner V A. Tenascin: does it play a role in epidermal morphogenesis and homeostasis? J Invest Dermatol 1994; 102:273–277 145. Mackie E J, Chiquet Ehrismann R, Pearson C A et al. Tenascin is a stromal marker for epithelial malignancy in the mammary gland. Proc Natl Acad Sci USA 1987; 84: 4621–4625 146. Shiraishi T, Kato H, Komada S et al. Tenascin expression and postnatal development of the human prostate. Int J Dev Biol 1994; 38:391–395 147. Xue Y, Umbas R, Aalders T et al. Tenascin expression in human prostate: is tenascin involved in tissue homeostasis? Urol Res 1995; 23:246 148. Xue Y, Ruijter E, Aalders T et al. Tenascin expression in prostatic intraepithelial neoplasia (PIN): is tenascin expression associated with tissue remodelling in prostatic neoplastic transformation? Urol Res 1995; 23:283 149. Weinstein M H, Partin A W, Veltri R W, Epstein J I. Neuroendocrine differentiation in prostate cancer: enhanced prediction of progression after radical prostatectomy. Hum Pathol 1996; 27:683–687 150. Timms B G, Mohs T J, Didio L J A. Ductal budding and branching patterns in the developing prostate. J Urol 1994; 151:1427–1432 151. Norman J T, Cunha G R, Sugimura Y. Induction of new ductal growth in adult prostatic epithelium in response to an embryonic prostatic inductor. Prostate 1986; 8: 209–220 152. Krieg M, Nass R, Tun S. Effect of aging on endogenous level of 5α-dihydrotestosterone, testosterone, estradiol, and estrone in epithelium and stroma of normal and hyperplastic human prostate (BPH). J Clin Endocrinol Metab 1993; 77:375–381 153. Vom Saal F S, Timms B G, Montano M M et al. Prostate enlargement in mice due to fetal exposure to a low dose of estradiol or diethylstilbestrol and opposite effects at high doses. Proc Natl Acad Sci USA 1997; 94:2056–2061 154. Griffiths K. Les oestrogenes et la prostate. In: Khoury S, Chatelain C (eds). Urologie. Paris: FIIS, 1988:308–332 155. Prins G S, Birch L. The developmental pattern of androgen receptor expression in rat prostate lobes is altered after neonatal exposure to estrogen. Endocrinology 1995; 136:1303–1314 156. Kuiper G G J M, Enmark E, Pelto-Huikko M et al. Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 1996; 93:5925–5930 157. Mosselman S, Polman J, Dijkema R. ERß: identification and characterisation of a novel human estrogen receptor. FEBS Lett 1996; 392:49–53 158. Green S, Walter P, Kumar V et al. Human oestrogen receptor cDNA sequence, expression and homology to verb-A. Nature 1986; 320:134–139 159. Kuiper G G J M, Carlsson B, Grandien J et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and ß. Endocrinology 1997; 138:863–870 160. Berry M, Metzger D, Chambon P. Role of the two activating domains of oestrogen receptor in the cell-type and promoter-context dependent agonistic activity of the antioestrogen 4-hydroxytamoxifen. EMBO J 1990; 9: 2811–2818 161. Tzukerman M T, Esty A, Santiso-Mere D et al. Human estrogen receptor transactivational capacity is determined by both cellular and promoter-context and mediated by two functionally distinct intramolecular regions. Mol Endocrinol 1994; 8:21–30 162. Kraus W L, McInerny E M, Katzenellenbogen B S. Ligand-dependent, transcriptionally productive file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_65.html[09.07.2009 11:51:47]
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association of the amino- and carboxy-terminal regions of a steroid hormone nuclear receptor. Proc Natl Acad Sci USA 1995; 92:12314–12318 163. Montano M M, Muller V, Trobaugh A, Katzenellenbogen B S. The carboxy-terminal F domain of the human estrogen receptor: role in the transcriptional activity of the receptor and the effectiveness of antiestrogens as estrogen antagonists. Mol Endocrinol 1995; 9:814–825 164. Katzenellenbogen J A, O’Malley B W, Katzenellenbogen B S. Tripartite steroid hormone receptor pharmacology: interaction with multiple effector sites as a base for the cell- and promoter-specific action of these hormones. Mol Endocrinol 1996; 10:119–131
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Page 66 165. Iafrati M D, Karas R H, Aronovitz M et al. Estrogen inhibits the vascular injury response in estrogen receptor alpha-deficient mice. Nature Med 1997; 3:545–548 166. Palmer R M J, Ferrige A G, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987; 327:524–526 167. Bulkley G B. Reactive oxygen metabolites and reperfusion injury: aberrant triggering of reticuloendothelial function. Lancet 1994; 344:934–936 168. Moretto M, Lopez F J, Negro-Vilar J. Nitric oxide regulates luteinizing hormone-releasing hormone secretion. Endocrinology 1993; 133:2399–2402 169. Moncada S. Nitric oxide: discovery and impact on clinical medicine. J R Soc Med 1999; 92:164–169 170. Rajfer J, Aronson W J, Bush P A et al. Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to noradrenergic, noncholinergic neurotransmission. N Engl J Med 1992; 326:90–94 171. Shaw R I, Papka R E, McNeill D L, Yee J A. NADPH-diaphorase positive nerves and the role of nitric oxide in CGRP relaxation of uterine contraction. Peptides 1993; 14:637–641 172. Suarez-Pinzon W L, Strynadka K, Schulz R, Rabinovitch A. Mechanisms of cytokine-induced destruction of rat insulinoma cells: the role of nitric oxide. Endocrinology 1994; 134:1006–1010 173. Kyprianou N, Litvak J P, Borkowski A et al. Induction of prostate apoptosis by doxazosin in benign prostatic hyperplasia. J Urol 1998; 159:1810–1815 174. Sarafian TA, Bredesen DE. Is apoptosis mediated by reactive oxygen species? Free Radic Res 1994; 20:1–6 175. Klebanoff S J. Oxygen metabolites from phagocytes. In: Gallin J I, Goldstein I M, Snyderman R (eds). Inflamation: basic principles and clinical correlates, 2nd edn. New York: Raven Press, 1992:541– 588 176. Hibbs J B, Taintor R R, Vavrin Z, Rachlin E M. Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun 1988; 157:87–94 177. El Etreby M F, Habenicht U F. The function and the role of aromatase inhibitors in the treatment of BPH. In: Kurth K, Newling DWW (eds). Benign prostatic hyperplasia. New York: Wiley-Liss, 1994:209– 230 178. Del Vecchio S, Ulissi A. Faecal elimination of steroids in rats after oral administration of mepartricin. J Int Med Res 1990; 18:468–478 179. Shakutou S, Bandoh K, Yoshinaka Y et al. Effect of mepartricin, a polyene macrolide agent, on fecal excretion and serum concentration of estrogen and number of prostatic estrogen receptors in immature rats. Prostate 1999; 38: 17–27 180. Lotti T, Mirone V, Prezioso D et al. Observations on some hormone fractions in patients with BPH treated with mepartricin. Curr Ther Res 1988; 44:402–406 181. Denis L, Pagano F, Nonis A et al. Double-blind, placebocontrolled trial to assess the efficacy and tolerability of mepartracin in the treatment of BPH. Prostate 1998; 37: 246–252 182. McConnell J, Bartsch G, Debruyne F et al. Hormonal treatment of benign prostatic hyperplasia. In: Cockett A T K, Aso Y, Chatelain C et al. (eds). First international consultation on benign prostatic hyperplasia. Paris: SCI, 1991:179–191 183. White J J, Neuwirth H, Miller CD, Schneider EL. DNA alterations in prostatic adenocarcinoma and benign prostatic hyperplasia: detection by DNA fingerprint analyses. Mutat Res 1990; 237:37–43 184. de Vere White R W, Gumerlock P H, Chi S G, Meyers F J. p53 Tumor suppressor gene abnormalities are frequent in human prostatic tissues. J Urol 1993; 149:376A 185. Bedford M T, van Helden P D. Hypomethylation of DNA in pathological conditions of the human prostate. Cancer Res 1987; 47:5274–5276 186. Muller W J, Lee F S, Dickson C et al. The int-2 gene product acts as an epithelial growth factor in transgenic mice. EMBO J 1990; 9:907–913 187. Tutrone R F, Ball R A, Ornitz D M et al. Benign prostatic hyperplasia in a transgenic mouse: a new hormonally sensitive investigatory model. J Urol 1993; 149:633–639 188. Sanda M G, Beaty T H, Stutzman R E et al. Genetic susceptibility of benign prostatic hyperplasia. J Urol 1994; 152:115–119 189. Partin A W, Page W F, Lee B R et al. Concordance rates for benign prostatic disease among twins suggest hereditary influence. Urol 1994; 44:646–650 190. Sanda M G, Doehring C B, Binkowitz B et al. Clinical and biological characterization of familial benign prostatic hyperplasia. J Urol 1997; 157:876–879 191. Doehring C B, Sanda M G, Partin A W et al. Histopathologic characterization of hereditary benign file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_66.html[09.07.2009 11:51:48]
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prostatic hyperplasia. Urology 1996; 48:650–653 192. Griffiths K, Adlercreutz H, Boyle P et al. Nutrition and cancer. Oxford: Isis Medical Media, 1996 193. Griffiths K, Denis L J, Turkes A. Oestrogens, phytooestrogens and pathogenesis of prostatic disease. London: Martin Dunitz, 2002 194. Haenzel W, Kurihara M. Studies of Japanese migrants. I. Mortality from cancer and other diseases among Japanese in the United States. J Natl Cancer Inst 1968; 40:43–68 195. Shimizu H, Ropp R K, Bernstein L et al. Cancers of the breast and prostate among Japanese and white immigrants in Los Angeles County. Br J Cancer 1991; 63:963–966
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Page 67 196. Bradbury R B, White D C. Oestrogens and related substances in plants. Vit Horm 1954; 12:207–233 197. Price K R, Fenwick G R. Naturally occurring oestrogens in food—a review. Food Add Contam 1985; 2:73–106 198. Verdeal K, Brown R R, Richardson T, Ryan D S. Affinity of phytoestrogens for estradiol-binding proteins and effect of coumestrol on growth of 7, 12-dimethylbenz(a) anthracene-induced rat mammary tumors. J Natl Cancer Inst 1980; 64:285–290 199. Axelson M, Sjovall J, Gustafsson B E, Setchell K D R. A dietary source of the non-steroidal oestrogen equol in man and animals. J Endocrinol 1984; 102:49–56 200. Setchell K D R, Adlercreutz H. Mammalian lignans and phytooestrogens. Recent studies on their formation, metabolism and biological role in health and disease. In: Rowland IR (ed). Role of gut flora in toxicity and cancer. London: Academic Press, 1988:315–345 201. Walz E. Isoflavon- und Sapogenin-Glucoside in Sojahispida. Justus Liebigs Annal Chem 1931; 489: 118–155 202. Coward L, Barnes N C, Setchell K D R, Barnes S. Genistein, daidzein, and their β-glycoside conjugates: antitumor isoflavones in soybean foods from American and Asian diets. J Agric Food Chem 1992; 41:1961–1967 203. Rosenblum E R, Campbell I M, Van Thiel D H, Gavaler J S. Isolation and identification of phytoestrogens from beer. Alcoholism Clin Exp Res 1992; 16:843–845 204. Van Thiel D H, Galvao-Teles A, Monteiro E et al. The phytoestrogens present in de-ethanolised bourbon are biologically active: a preliminary study in postmenopausal women. Alcoholism Clin Exp Res 1991; 15:822–823 205. Rao C B S (ed). The chemistry of lignans. Waltair, India: Andra University Press and Publications, 1978:1–377 206. Thompson L U, Robb P, Serraino M, Cheung F. Mammalian lignan production from various foods. Nutr Cancer 1991; 16:43–45 207. Pumford S L, Morton M M, Turkes A, Griffiths K. Determination of the isoflavonoids genistein and daidzein in biological samples by gas chromatography-mass spectrometry. Anal Clin Biochem 2002; 39:281–292 208. Grace P B, Taylor J I, Botting N P et al. Quantification of isoflavones and lignans in urine using gas chromatography/mass spectrometry. Anal Biochem 2003; 315: 114–121 209. Adlercreutz H, Fotsis T, Bannwart C et al. Determination of urinary lignans and phytoestrogen metabolites, potential antiestrogens and anticarcinogens, in urine of women on various habitual diets. J Steroid Biochem 1986; 25: 791–797 210. Morton M S, Wilcox G, Wahlquvist M L, Griffiths K. Determination of lignans and isoflavonoids in human female plasma following dietary supplementation. J Endocrinol 1994; 142:251–259 211. Finlay E M H, Wilson D W, Adlercreutz H, Griffiths K. The identification and measurement of phytooestrogens in human saliva, plasma, breast aspirate or cyst fluid, and prostatic fluid using gas chromatography-mass spectrometry. J Endocrinol 1991; 129 (Suppl): 49 212. Dehennin L, Reiffsteck A, Joudet M, Thibier M. Identification and quantitative estimation of a lignan in human and bovine semen. J Reprod Fert 1982; 66: 305–309 213. Adlercreutz H, Honjo H, Higashi A et al. Urinary excretion of lignans and isoflavonoid phytoestrogens in Japanese men and women consuming traditional Japanese diet. Am J Clin Nutr 1991; 54:1093–1100 214. Adlercreutz H, Markkanen H, Watanabe S. Plasma concentrations of phyto-oestrogens in Japanese men. Lancet 1993; 342:1209–1210 215. Setchell K D R, Borriello S P, Hulme P et al. Nonsteroidal oestrogens of dietary origin: possible roles in hormonedependent disease. Am J Clin Nutr 1984; 40:569–578 216. Turkes A, Denis L, Griffiths K. Can diet reduce the risk of prostate cancer? In: Bowsher W (ed). Challenges in prostate cancer. Oxford: Blackwell Science, 2000:3–18 217. Evans B A J, Griffiths K, Morton M. Inhibition of 5α-reductase and 17ß-hydroxysteroid dehydrogenase in genital skin fibroblasts by dietary lignans and isoflavonoids. J Endocrinol 1995; 147:295–302 218. Hiipakka R A, Zhang H Z, Dai W et al. Structure-activity relationships for inhibition of human 5alpha-reductase by polyphenols. Biochem Pharmacol 2002; 63:1165–1176 219. Adlercreutz H, Bannwart C, Wahala K et al. Inhibition of human aromatase by mammalian lignans and isoflavonoid phytoestrogens. J Steroid Biochem Molec Biol 1993; 44: 147–153 220. Brueggemeier R W, Gu X, Mobley J A et al. Effect of phytoestrogens and synthetic combinatorial file:///H|/...E8%FF/Textbook%20of%20Benign%20Prostatic%20Hyperplasia%202%20Ed%20Kirby%202005/files/page_67.html[09.07.2009 11:51:48]
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libraries on aromatase, estrogen biosynthesis, and metabolism. Ann NY Acad Sci 2001; 948:51–66 221. Akiyama T, Ishida J, Nakagawa S et al. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 1987; 262:5592–5595 222. Scholar E M, Toews M L. Inhibition of invasion of murine mammary carcinoma cells by the tyrosine kinase inhibitor genistein. Cancer Lett 1994; 87:159–162 223. Fotsis T, Pepper M, Adlercreutz H et al. Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proc Natl Acad Sci USA 1993; 90:2690–2694 224. Myoung H, Hong S P, Yun P Y et al. Anti-cancer effect of genistein in oral squamous cell carcinoma with respect to angiogenesis and in vitro invasion. Cancer Sci 2003; 94: 215–220
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Page 68 225. Rice-Evans C A, Miller N J, Bolwell P G et al. The relative antioxidant activities of plant-derived polyphenolic flavonoids. Free Radical Res 1995; 22:375–383 226. Wei H, Zhang X, Wang Y, Lebwohl M. Inhibition of ultraviolet light-induced oxidative events in the skin and internal organs of hairless mice by isoflavone genistein. Cancer Lett 2002; 185:21–29 227. McCabe M J Jr, Orrenius S. Genistein induces apoptosis in immature human thymocytes by inhibiting topoisomerase-II. Biochem Biophys Res Comm 1993; 194: 944–950 228. Constantinou A, Mehta R, Runyan C et al. Flavonoids as DNA topoisomerase antagonists and poisons: structure-activity relationships. J Nat Prod 1995; 58: 217–225 229. Messina M J, Persky V, Setchell K D R, Barnes S. Soy intake and cancer risk: a review of the in vitro and in vivo data. Nutr Cancer 1994; 21:113–130 230. Salti G I, Grewal S, Mehta R R et al. Genistein induces apoptosis and topoisomerase II-mediated DNA breakage in colon cancer cells. Eur J Cancer 2000; 36:796–802 231. Lamartiniere C A, Zhang J X, Cotreneo M S. Genistein studies in rats: potential for breast cancer prevention and reproductive and development toxicity. Am J Clin Nutr 1998; 68 (Suppl 6): 1400S-1405S 232. Zhou J R, Mukherjee P, Gugger E T et al. Inhibition of murine bladder tumorigenesis by soy isoflavones via alterations in the cell cycle, apoptosis, and angiogenesis. Cancer Res 1998; 58:5231– 5238 233. Cohen L A, Zhao Z, Pittman B, Scimeca J A. Effect of intact and isoflavone-depleted soy protein on NMU-induced rat mammary tumorigenesis. Carcinogenesis 2000; 21:925–935 234. Jin Z, MacDonald R S. Soy isoflavones increase latency of spontaneous mammary tumors in mice. J Nutr 2002; 132: 186–190
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Page 69 4 Molecular aspects of bening prostatic hyperplasia M R Freeman M E Gleave L W K Chung Introduction Despite research on benign prostatic hyperplasia (BPH) undertaken by a large number of laboratories and spanning nearly a century,1,2 the molecular mechanisms underlying the age-related enlargement of the prostate, and the cellular basis of BPH symptoms, are still obscure. In the last decade, however, there has been an explosive growth of new knowledge on molecular aspects of cellular growth control, the function of secreted and cell surface proteins, the regulatory role of the extracellular matrix, pathways of transmission of external signals to the cell interior and to the cell nucleus, and the mechanics of cell cycle regulation. Although much of this research has been carried out in other organ systems or in artificial models, increases in new findings using prostate-growth models in recent years have also provided important clues about potential mechanisms of prostatic neoplasia. There is now strong evidence that biochemical mediators sequestered or originating from within the prostatic connective tissue play a crucial role in the functional state and the growth potential of the mature gland. In the prostate and in other organ systems, both diffusible (soluble) and solid-state (insoluble) mediators are involved in tissue interactions responsible for differentiative change as well as changes in patterns of cell growth. The identification of some of these regulatory molecules, and in some cases the discovery of their specific functional roles, suggest the possibility that BPH occurs as a result of aberrant cellular interactions resulting from alteration in expression, localization, and function of cytokines and growth factors as well as insoluble regulatory molecules comprising the connective tissue matrix. In this review we provide an overview of the concept of stromal-(mesenchymal-) epithelial interaction as it pertains to development and growth of the prostate. We attempt to integrate findings from more classical studies of tissue and cell recombination with recent results from molecular investigations of cell regulation by soluble regulatory factors and the extracellular matrix (ECM). The objective of this treatment is to provide a framework for the development of testable hypotheses of the molecular processes underlying the clinical dilemma of BPH, with the ultimate goal of devising novel and effective therapies for this common neoplasm. Stromal-epithelial interactions in prostatic functional differentiation and growth The prostate gland is composed of two histologically distinct tissue compartments, a branching acinarductal epithelium and fibromuscular stroma. Morphometric analyses have demonstrated that each compartment (when luminal spaces are considered part of the epithelial compartment) makes up about one-half of the glandular volume of the human prostate.3 Each of these tissue elements is further comprised of a variety of cell types, including secretory and basal epithelial cells, smooth muscle cells, undifferentiated fibroblasts, vascular endothelial networks, nerve bundles, and inflammatory cell infiltrates. Each of these specialized cells can be further grouped by histologic criteria into distinct subcompartments, such as simple columnar vs pseudostratified epithelium, and vascular and connective smooth muscle. However, a precise categorization of all of the specialized cells in the prostate awaits the identification of more informative molecular markers than we have presently. None of the specialized cell types found within the human prostate has yet been thoroughly characterized in molecular terms. The prostatic stroma provides a supporting matrix for the ductal epithelial cells, which synthesize, concentrate, and secrete the components of the prostatic fluid into the ductal lumina. In addition, the connective-smooth-muscle compartment mediates the contractions which expel the prostatic secretions from the gland. There is strong evidence from experimental models that the stromal and epithelial compartments communicate with each other, and that prostatic growth and functional differentiation, both during development and in the adult, are dependent on regulatory signaling between them. The development of the prostate occurs in response to inductive signals originating from the endodermal urogenital sinus mesenchyme. In tissue recombination experiments, in which mouse fetal urogenital sinus (UGS) is microdissected into epithelial (UGE) and mesenchymal (UGM) components, prostatic growth, morphogenesis, and functional differentiation occur when homotypic (prostatic) or certain types of heterotypic epithelia are recombined with UGM and implanted under the kidney
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Page 70 capsule of a syngeneic or athymic host.4–10 Under these conditions, reconstituted prostatic tissue is formed, with histomorphologic and immunohistochemical evidence of normal glandular architecture and secretory functions. Prostatic morphogenesis does not occur in the absence of UGM, or in the presence of noninductive heterotypic mesenchymes, indicating a high degree of tissue or developmental specificity underlying the morphologic outcome of these experiments.11 These tissue-specific inductive mechanisms are highly conserved in evolution, as demonstrated by the capability of human fetal bladder epithelium to differentiate into ductal structures lined by columnar epithelium in response to heterotypic recombination with mouse UGM.7 It is now well established that fetal prostatic development and morphogenesis is absolutely dependent on inductive signals originating from the mesenchymal compartment. This is consistent with similar findings in other organ systems.8,12 Remarkably, however, the ability of adult epithelia to respond functionally to these inductive signals has also been demonstrated for adult prostatic, seminal vesicle, ureter, and bladder epithelium.4,5,9,10,13–15 These studies have demonstrated directly that adult urogenital epithelia maintain the capability to respond to stromal mediators of growth and differentiation. This conclusion is consistent with the hypothesis, first proposed by McNeal,16 that benign prostatic growth occurring later in life in humans is the result of a ‘reawakening’ of the inductive potential of the prostatic stroma. There is general agreement that BPH is mediated in part by gonadal androgens. Boys castrated prepubertally do not develop BPH.17 The prostate is an androgendependent organ and circulating androgens are required for maintenance of prostatic function in adulthood and for embryonic and fetal prostatic development.18 The rat prostate, which is primarily a parenchymal organ with an epithelial:stromal ratio of 5:1, loses approximately 80% of its cellular content after castration.19 Based on a variety of studies of prostatic dependence and response to androgens, the epithelial compartment appears to be more sensitive to the effects of androgen withdrawal than the stromal compartment. This correlates with the observation that high-affinity androgen receptors are more abundant in the adult prostatic epithelium than in the neonatal prostatic stroma or in the mature prostate of the adult20,21 However, during fetal prostatic development, androgen receptors are expressed exclusively in the mesenchyme,21,22 indicating that androgen-mediated effects on development of prostatic epithelial ductal growth and morphogenesis are proximally regulated by androgenreceptor-mediated mechanisms confined initially to the mesenchymal compartment. This was demonstrated most dramatically by recombination experiments in which androgen-receptor-deficient bladder epithelium (Tfm/y) was recombined heterotypically with androgen-receptorpositive UGM, resulting in dramatic growth and prostatic functional differentiation in the epithelium.9,23–25 These results demonstrate that mesenchyme-mediated regulation of epithelium is not only permissive, in which epithelial glandular morphogenesis occurs in cells previously committed to expressing a prostatic phenotype. In addition, these findings indicate that mesenchymal-epithelial interactions can also be instructive, in which epithelium previously directed to a distinct, nonsecretory, nonglandular lineage is nevertheless capable of expressing a heterotypic, secretory phenotype specified by the adjacent mesenchyme. Studies on androgen receptor localization in these reconstituted prostatic tissues have confirmed the absence of androgen receptors in the epithelial compartment, and the presence of androgen receptors (identified by binding analyses revealing the presence of functional, high-affinity androgen-binding sites) in the mesenchyme.24,25. A critical role for the mesenchyme in prostatic development parallels studies on the mechanisms of hormonally-induced regression of the mammary gland, in which steroid hormone-mediated degenerative responses in the parenchyma are mediated by the mesenchyme.12,26,27 Similarities between the prostate and mammary gland in cellular and molecular mechanisms of organ function are of interest in the study of prostatic disease because of the functional, structural, and endocrinological similarities between these two organs.11 The tissue specificity of inductive mesenchymal-epithelial interactions was demonstrated by tissue recombination experiments in which mammary gland and preputial gland mesenchyme were each capable of eliciting dramatic growth and cytodifferentiation of mammary epithelium in vivo, while other mesenchymes (vaginal, uterine, UGS, genital tubercle) were either incapable of inducing growth, or induced an aberrant histomorphologic architecture.8 There is also experimental evidence that the epithelial tissue compartment is capable of directing events in neighboring mesenchyme. Tissue recombination experiments similar to those described above have recently provided evidence that spatial organization of urogenital smooth muscle involves critical, tissuespecific paracrine mediation from the neighboring epithelium.28 The potential for stromal mediation of neoplastic growth has also been demonstrated with experimental
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Page 71 models. Chung and collaborators have presented results of a series of studies using cell recombination techniques which show that the presence of stromal cells greatly enhances neoplastic growth of immortalized epithelial cells or adenocarcinoma cells in vivo.15,29–34 In these experiments, carcinomas or carcinosarcomas are created experimentally in syngeneic or athymic rodent hosts by in vivo injection of epithelial cells in a co-inoculum with homotypic or heterotypic fibroblasts cultured in vitro. Tumorigenic potential and tumor growth rate are subsequently measured directly. Initially, Chung et al.29 demonstrated the potential for tumorigenic rat prostate fibroblasts to evoke neoplastic growth in vivo of nontumorigenic rat prostate-derived epithelial cells. Subsequent studies demonstrated the potential for heterotypic fibroblasts to accelerate the growth of human prostate, breast, bladder, and kidney carcinoma cells when co-inoculated subcutaneously in athymic hosts.30 Using the androgenreceptor-positive LNCaP cell line, which expresses the androgen-regulated prostate-specific proteinase, prostate-specific antigen (PSA), Gleave et al.32 demonstrated the capability of prostate and bone fibroblasts, but not lung and kidney fibroblasts, to induce PSAsecreting tumors in vivo. In this study, LNCaP tumors grew preferentially in male hosts, suggesting a role for androgens in fibroblast-mediated acceleration of epithelial tumor growth. An inductive role for the organ-specific microenvironment in prostate tumor growth was also shown in studies where LNCaP tumors were generated within prostatic tissue by orthotopic inoculation into mouse dorsal prostate.33 In these studies, PSA-secreting tumors did not form when LNCaP cells were injected under the renal capsule or under the skin, even when higher numbers of tumor cells were injected at these ectopic sites. The capability for mouse prostate to serve as a preferred site for growth of human prostate tumor cells also suggests that inductive stromal influences on prostate tumor growth are evolutionarily conserved. Intraprostatic implantation of human prostate tumor cells has also been demonstrated to result in enhanced rates of tumor metastasis to distant sites,35 consistent with the idea that the prostatic environment contains regulatory factors which can enhance tumor development and progression to the metastatic state. In contrast to the above studies, which demonstrate the capability of stromal cells to promote normal and neoplastic growth of prostatic epithelial cells, mesenchyme has also been shown to induce differentiation of transplantable rat prostatic tumors carried in animals for decades. UGM was able to induce glandular, secretory, and biochemical differentiation of androgen-sensitive, well-differentiated Dunning prostatic tumors, but not the poorly differentiated, androgen-independent Dunning and Noble prostatic tumors.36,37 This induction of histomorphologic and functional differentiation in a tumor of nearly historic origin (the Dunning tumor has been passaged in animals continuously for over 30 years) is likely to be tissue-specific, based on the failure of neonatal bladder mesenchyme to induce differentiation of tumor in Dunning tumor-bladder mesenchyme chimeras.37 These studies are consistent with reports from other laboratories demonstrating the capability of embryonic tissues to induce the differentiation of a variety of neoplasms, including embryonal carcinoma,38 colon carcinoma,39 neuroblastoma,40 and mammary carcinoma.41 Induction of carcinoma cell differentiation by stroma provides an intriguing contrast to the growth-promoting role of fibroblasts in carcinomas created by in vivo injections of single cell suspensions. These differences illustrate the limitations of model systems in extrapolating directly to the clinical situation. However, they also provide clear demonstrations of the potential for in vivo growth of tumors to be altered in drastic ways by the stromal microenvironment. The role of soluble growth factors The results presented above are consistent with the hypothesis that mesenchyme-derived paracrine factors direct growth, branching morphogenesis, and secretory function of prostatic epithelium during critical phases of prenatal and adult life. A common assumption is that enlargement of tissues occurs as a result of the paracrine activity of one or more growth factors, soluble polypeptides belonging to a spectrum of gene families which stimulate proliferation of cells in culture. This is partly correct, but nevertheless it is a highly oversimplified assumption. Most of the molecules identified as growth factors by functional criteria using in vitro systems actually show a wide range of biological activities in cell culture, depending on the experimental conditions or on the cell types used for analysis. Further, for many of these factors, evidence from in vivo systems indicates that their roles in development, tissue homeostasis, or wound repair may be distinctly different or even unrelated to the control of cell growth per se. Basic fibroblast growth factor (historically abbreviated bFGF, but more recently known as FGF-2) is a pleoitropic polypeptide capable of stimulating the proliferation of a variety of cultured cells,42 including human prostate stro mal cells.43 FGF-2 also induces endothelial cell growth in vitro, initiates neovascularization in vivo, and is an
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Page 72 important tumor angiogenesis factor. FGF family members are important mediators of mesoderm patterning, organ growth and differentiation, and bone formation,44 however, from in vitro studies of FGFs alone, it would have been difficult to predict these important developmental roles for this growth factor family. The reader is directed to a comprehensive review on growth factors in relation to prostatic and urological neoplasia for an overview.45 The pleiotropic nature of most growth factors makes it difficult to construct hypotheses regarding the potential role of one single growth factor on specific forms in BPH. Although the prostatic volume enlarges in benign hyperplasia in humans, physiologic changes such as remodeling of the microvasculature46 and relative increases in the nonmuscular (fibroblastic) compartment of the prostatic stroma3 have also been reported. These and other findings in experimental systems suggest that BPH is a complex physiologic process involving growth and remodeling of tissue architecture, and involving bladder outlet obstruction as well as bladder dysfunction.47 Individual growth factors might therefore play multiple roles while other growth factors, although present, may play no functional role in BPH. Studies of growth factor localization and function in human and rodent prostatic tissues have been less common than studies with cultured cell lines. To date, few differences between growth factor levels in human BPH and normal prostatic tissue have been reported. In some reports, where investigators used mRNA expression techniques to examine growth factor or growth factor receptor levels, no differences between normal and BPH tissues were found.48,49 One of the best studied examples of a single factor that is capable of mediating a wide range of distinct activities in vitro and in vivo is transforming growth factor β1 (TGFβ1). TGFβ1 is a member of a family of growth and differentiation factors which includes the related but genetically distinct isoforms TGFβ2 and TGFβ3 in mammals, and a variety of other molecules such as Mullerian inhibiting substance (involved in masculinization during fetal development), activins, inhibins, and bone morphogenetic proteins.50 The identification of TGFβ-related molecules as mediators of cell differentiation exemplifies the role of growth factors in normal developmental processes unrelated to cell growth. TGFβ1 is a potent mitogen for fibroblasts and other mesenchymal cell types, but may also be the most important physiologic inhibitor of epithelial cell proliferation. TGFβ1 also regulates extracellular matrix biosysnthesis and degradation, is a potent immunosuppressor, and can stimulate cells to undergo apoptosis. Carcinoma cells, including prostate tumor cells, often lose their normal pattern of growth inhibition in response to TGFβ1.51,52 The TGFβ insensitivity of carcinoma cells is thought to be an important mechanism of tumor expansion during malignant progression. TGFβ1 may also enhance the invasive potential of tumor cells,53 thereby promoting malignant progression by a mechanism not directly related to an absence of its normal growthinhibitory function. It is clear from studies of the diverse biological activities of TGFβ1, and of a host of other growth factors belonging to different gene families, that the physiologic activities of specific growth factors in vivo are dependent on the temporal and spatial context in which they act. It has been proposed that alteration in the functional status of TGFβ1 in prostatic tissue may play a role in BPH. Although TGFβ1 can positively regulate prostate stromal cell growth, it also upregulates the production of FGF-2, an autocrine growth factor for prostate stromal cells.43,54 Therefore, this growth factor axis, which consists of mechanisms for both positive and negative effects on stromal cell proliferation, could be altered during the natural history of BPH to favor expansion of the stromal compartment. TGFβ1 has been found in human seminal plasma, suggesting that it is a secretory product of the normal prostate gland.55 Enforced expression of TGFβ1 in vivo in reconstituted mouse prostate by retroviral transfection resulted in proliferative abnormalities in the epithelial and stromal compartments, but with no overall change in tissue growth.56 Elevation of TGFβ isoform accumulation has been observed in human prostate cancer and in rodent prostatic tumors.57–59 Human and rat prostate cell lines and normal and neoplastic tissues also express TGFβ-like bone morphogenetic protein mRNAs.60 In the developing mouse prostate, TGFβ-1, -2, and -3 isoforms were detected in UGM, with expression levels appearing higher in UGM than in UGE.61 During development, highest levels of TGFβ1 were found at epithelial—mesenchymal interfaces in areas of active epithelial branching morphogenesis, suggesting a role for the growth factor in morphogenesis of the ductal network and in epithelial differentiation. Expression of the TGFβ1 isoform was retained, predominantly in the mesenchyme, in the adult. Expression patterns of TGFβ isoforms in development have also suggested a role for these factors in mesenchymal-epithelial interactions outside of the developing urogenital tract.62 The potential for TGFβ isoforms to regulate smooth muscle cell physiology63 suggests the possibility that TGFβ-related factors may be physiologic regulators of prostatic smooth muscle cells in vivo. An indirect role for TGFβ in tissue growth can also be inferred
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Page 73 from studies in which TGFβ has been shown to upregulate production of angiogenic factors by vascular smooth muscle cells.64 Increases in TGFβ receptor mRNA have been reported in BPH patients treated with finasteride, suggesting the involvement of the TGFβ axis in the glandular atrophy seen histologically with
