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TRANSFORMING GROWfH FACTOR-P IN CANCER THERAPY, VOLUME I CANCER DRUG DISCOVERY AND DEVELOPMENT Beverly A. Teicher, PhD, SERIES EDITOR Checkpoint Responses in Cancer Therapy, edited by Cancer Chemoprevention, Volume 2: Strategies for Wei Dai, 2008 Cancer Chemoprevention, edited by Gary J. Kelloff, Cancer Proteomics: From Bench to Bedside, edited by Ernest T. Hawk, and Caroline C. Sigman, 2005 Sayed S. Daoud, 2008 Death Receptors in Cancer Therapy, edited by Wafik S. Transforming Growth Factor-B in Cancer Therapy, El-Deiry, 2005 Volume II: Cancer Treatment and Therapy, edited Cancer Chemoprevention, Volume 1: Promising Cancer by Sonia Jakowlew, 2008 Chemopreventive Agents, edited by Gary J. Kelloff, Transforming Growth Factor-B in Cancer Therapy, Ernest T. Hawk, and Caroline C. Sigman, 2004 Volume 1: Basic and Clinical Biology, edited by Proteasome Inhibitors in Cancer Therapy, edited by Sonia Jakowlew, 2008 Julian Adams, 2004 Microtubule Targets in Cancer Therapy, edited by Nucleic Acid Therapeutics in Cancer, edited by Alan M. Antonio T. Fojo, 2008 Gewirtz, 2004 Antiangiogenic Agents in Cancer Therapy, Second DNA Repair in Cancer Therapy, edited by Lawrence C. Edition, edited by Beverly A. Teicher and Lee M. Panasci and Moulay A. Alaoui-Jamali, 2004 Ellis, 2007 Hematopoietic Growth Factors in Oncology: Basic Apoptosis and Senescence in Cancer Chemotherapy Science and Clinical Therapeutics, edited by and Radiotherapy, Second Edition, edited by George Morstyn, MaryAnn Foote, and Graham J. David A. Gerwitz; Shawn Edan Holtz, and Steven Lieschke, 2004 Grant, 2007 Handbook of Anticancer Pharmacokinetics and Molecular Targeting in Oncology, edited by Howard L. Pharmacodynamics, edited by William D. Figg Kaufman, Scott Wadler, and Karen Antman, 2007 and Howard L. McLeod, 2004 In Vivo Imaging of Cancer Therapy, edited by Anticancer Drug Development Guide: Preclinical Anthony F. Shields and Patricia Price, 2007 Screening, Clinical Trials, and Approval, Second Cytokines in the Genesis and Treatment of Cancer, Edition, edited by Beverly A. Teicher and Paul A. edited by Michael A. Caligiuri, Michael T. Lotze, Andrews, 2004 and Frances R. Balkwill, 2007 Handbook of Cancer Vaccines, edited by Michael A. Regional Cancer Therapy, edited by Peter M. Schlag and Morse, Timothy M. Clay, and Kim H. Lyerly, 2004 Ulrike Stein, 2007 Drug Delivery Systems in Cancer Therapy, edited by Gene Therapy for Cancer, edited by Kelly K. Hunt, Dennis M. Brown, 2003 Stephan A. Vorburger, and Stephen G. Swisher, Oncogene-Directed Therapies, edited by Janusz Rak, 2003 2007 Cell Cycle Inhibitors in Cancer Therapy: Current Deoxynucleoside Analogs in Cancer Therapy, edited by Strategies, edited by Antonio Giordano and Godefridus J. Peters, 2006 Kenneth J. Soprano, 2003 Cancer Drug Resistance, edited by Beverly A. Teicher, 2006 Chemoradiation in Cancer Therapy, edited by Hak Histone Deacetylases: Transcriptional Regulation and Choy, 2003 Other Cellular Functions, edited by Eric Verdin,2006 Fluoropyrimidines in Cancer Therapy, edited by Youcej Immunotherapy ofCancer, edited by Mary L. Disis, 2006 M. Rustum, 2003 Biomarkers in Breast Cancer: Molecular Diagnostics Targets for Cancer Chemotherapy: Transcription Factors for Predicting and Monitoring Therapeutic Effect, and Other Nuclear Proteins, edited by Nicholas edited by Giampietro Gasparini and Daniel F. B. La Thangue and Lan R. Bandara, 2002 Hayes, 2006 Tumor Targeting in Cancer Therapy, edited by Michel Protein Tyrosine Kinases: From Inhibitors to Useful Page, 2002 Drugs, edited by Doriana Fabbro and Frank Hormone Therapy in Breast and Prostate Cancer, edited McCormick, 2005 by v: Craig Jordan and Barrington J. A. Furr, 2002 Bone Metastasis: Experimental and Clinical Therapeutics, Tumor Models in Cancer Research, edited by Beverly A. edited by Gurmit Singh and Shajaat A. Rabbani, Teicher, 2002 2005 Tumor Suppressor Genes in Human Cancer, edited by The Oncogenomics Handbook, edited by William J. David E. Fisher, 2001 LaRochelle and Richard A. Shimkets, 2005 Matrix Metalloproteinase Inhibitors in Cancer Therapy, Camptothecins in Cancer Therapy, edited by edited by Neil J. Clendeninn and Krzysrto] Thomas G. Burke and Val R. Adams, 2005 Appelt, 2001 Combination Cancer Therapy: Modulators and Farnesyltransferase Inhibitors in Cancer, edited by Said Potentiators, edited by Gary K. Schwartz, 2005 M. Sebti and Andrew D. Hamilton, 2001 II TRANSFORMING GROWTH FACTOR-Ii IN CANCER THERAPY, VOLUME I BASIC AND CLINICAL BIOLOGY Edited by SONIA B. JAKOWLEW, PhD Cancer Training Branch, Office ofCenters, Training and Resources, National Cancer Institute, Bethesda, MD Foreword by MICHAEL B. SPORN, MD DepartmentofPharmacology, Dartmouth MedicalSchool, Hanover, NH © 2008 Humana Press 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 All rights reserved. www.humanapress.com All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. The content and opinions expressed in this book are the sole work of the authors and editors, who have warranted due diligence in the creation and issuance of their work. The publisher, editors, and authors are not responsible for errors or omissions or for any consequences arising from the information or opinions presented in this book and make no warranty, express or implied, with respect to its contents. Due diligence has been taken by the publishers, editors, and authors of this book to assure the accuracy of the informa- tion published and to describe generally accepted practices. The contributors herein have carefully checked to ensure that the drug selections and dosages set forth in this text are accurate and in accord with the standards accepted at the time of publication. Notwithstanding, since new research, changes in government regulations, and knowledge from clinical experience relating to drug therapy and drug reactions constantly occur, the reader is advised to check the product information provided by the manufacturer of each drug for any change in dosages or for additional warnings and contra- indications. This is of utmost importance when the recommended drug herein is a new or infrequently used drug. It is the responsibility of the treating physician to determine dosages and treatment strategies for individual patients. Further, it is the responsibility of the health care provider to ascertain the Food and Drug Administration status of each drug or device used in their clinical practice. The publishers, editors, and authors are not responsible for errors or omissions or for any consequences from the application of the information presented in this book and make no warranty, express or implied, with respect to the contents in this publication. This publication is printed on acid-free paper. e ANSI 239.48-1984 (American National Standards Institute) Permanence of Paper for Printed Library Materials. Production Editor: Michele Seugling Cover design by Nancy Fallatt For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact Humana at the above address or at any of the following numbers: Tel: 973-256-1699; Fax: 973-256-8341; or visit our Website: http://humanapress.com Photocopy Authorization Policy: Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Humana Press., provided that the base fee of US $30.00 per copy is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license from the CCC, a separate system of payment has been arranged and is acceptable to Humana Press. The fee code for users of the Transactional Reporting Service is: [978-1-58829-714-3/08 $30.00]. Printed in the United States of America. 10 9 8 7 6 5 4 3 2 e-ISBN: 978-1-59745-292-2 Library of Congress Control Number: 2007931768 IN MEMORIAM All of us in the transforming growth factor-f (TGF-~) research community were deeply saddened to learn of the death of Anita B. Roberts on May 26, 2006. Ironically, Anita died from cancer, a disease that is now closely linked to the peptide growth factor she and her colleagues discovered in the early 1980s and that will forever be associated with her name. As I reflect on her life and her contributions to science, three memories stand out that I believe illustrate the extraordinary person that Anita was. I first met Anita in Mike Sporn's office at the NCI in the summer of 1984. I was a young scientist working for a biotechnology company in the Bay Area of California. Our research team had discovered two growth factors, designated Chondrogenic Induction Factors A and B (CIF-A and CIF-B), that appeared to be highly related to a growth factor called TGF-~ that had been recently purified and characterized by Anita. Several of my colleagues and I met with Mike and Anita to share our data with them and to discuss how we might collaborate to more clearly elucidate the relationships between TGF-~, CIF-A and CIF-B. Eventually we determined that CIF-A was TGF-~l and CIF-B was TGF-~2. I clearly remember in my first meeting with Anita, her high levels of intensity, inquisitiveness, and energy. I was also struck by her scientific rigor and attention to detail. These were professional characteristics that would become hallmarks of her scientific career during the next 22 years. A second memory I have of Anita was related to a Wound Healing Society meeting we attended together in the early 1990s in Richmond, Virginia. One evening, several of us ended up in a "drinking establishment" listening to a Blue Grass band. Late in the evening, Anita and I walked back to the hotel where we were staying, when I asked her about her family, since all we ever seemed to talk about was science. Anita told me that she married her husband Bob who she had first met when she was a freshman in high school. It was clear to me that she loved her husband and children very much and was very proud of their accomplishments. It was refreshing for me to see someone who was both successful in the pursuit of their career and, at the same time, so committed to their family life. One of my final memories of Anita was at the 2005 Keystone Symposium on TGF-p that Anita, Mike Sporn and I had co-organized. Shortly after the three of us had agreed to organize the meeting, Anita was diagnosed with gastric carcinoma. I was stunned by the news and remember lying awake that night trying to imagine how Anita must feel. Given her prognosis, I thought it was unlikely she would survive the next 12 months to even attend the meeting. Much to my amazement, not only did Anita attend, but she sat with me during the entire meeting completely immersed in the science and reminiscing about how the TGF-~ field had progressed during the past 25 years. Anita's attendance at that meeting and another TGF-~ meeting held in San Diego in February, 2006, symbolized her incredible courage, determination, and perseverance. Anita was truly a remarkable individual. She exhibited an unusual balance of scientific brilliance and humility. She was a very caring and loving person who changed the lives of many of the people she touched. For those of us working in the field of TGF-~, her v vi In Memoriam death is a terrible loss. On the other hand, Anita would want us to "press on," to explore the unknown and determine whether this growth factor she discovered 25 years ago is a valid therapeutic target for diseases like cancer and pathological fibrosis. This will continue to be a difficult mission, but remembering Anita's personal and professional qualities should fortify our efforts and sustain us when we are discouraged. Although Anita is no longer with us, her indomitable spirit lives on to provide us inspiration and hope. John M McPherson, PhD FOREWORD Transforming Growth Factor-jl in Cancer Therapy, Volume I: Basic and Clinical Biology The present volume brings together a wealth of information that is fundamental to understanding the role ofTGF-~ in the pathogenesis, prevention, and treatment of cancer. It is not even 25 years since TGF-~ was first isolated and characterized as a dimeric pep- tide from both human and bovine sources (1-3), but the entire field ofTGF-~ research has grown and expanded so that it is now a central theme in all of cell biology. There is almost no tissue or organ in the mammalian body in which TGF-~ does not playa central role in embryonic differentiation or in adult function, and furthermore, malfunction of the normal physiology ofTGF-~ can have disastrous consequences in almost all of these sites. Therefore, the present comprehensive review of so many aspects of TGF-~ function is a most welcome attempt to bring together a huge body of experimental data that is of the utmost importance in the field of oncology. There are 45 chapters in this volume, which start with the most fundamental aspects of the molecular biology of TGF-~, with particular emphasis on the critical role of the unique receptors for TGF-~ and Smad signaling. Furthermore, a full 13 chapters are devoted to members of the TGF-~ superfamily (other than TGF-~ itself), including bone morphogenetic proteins, activins, inhibins, and Mullerian inhibiting substances, all of which have multifunctional actions that resemble those of TGF-~ and which signal through similar Smad pathways. The concluding 14 chapters deal with specific aspects of TGF-~ in inflammation and fibrosis, processes that are intimately involved with the genesis and metastasis of carcinoma. Thus, the reader of this volume will be treated to an unusual and unique overview of the role of TGF-~ in basic and clinical cancer biology. The topic is an extremely com- plicated one because of the multifunctional nature of TGF-~. As we have noted many times before (4), TGF-p may be considered the prototypical multifunctional signaling molecule. As is the case for all the other peptide growth factors, it is an element of a complex biological signaling language, providing the basis for intercellular (and perhaps even intracellular) communication in higher organisms. Like a symbol or a letter of the alphabet in a language or code, the meaning of the action of TGF-p can only be consid- ered in a cellular context. TGF-p always acts as a member of a set of other signals, and to understand its action, one must always consider the biological context in which it acts. The successful manipulation of TGF-~ for control of cancer will depend on under- standing this biological context, because TGF-~ has unique potential, both to suppress, as well as to enhance, the development and progression of malignancy. Many problems in TGF-~ physiology still remain unanswered (5). One of the most notable problems is the role of the TGF-~ that is found intracellularly, most particularly in mitochondria. Mitochondrial TGF-~ simply does not fit into the classical receptor/ Smad signaling paradigm, and has unfortunately received relatively little attention. Vll viii Foreword However, given the emphasis on the role of TGF-p in apoptosis, and the importance of mitochondrial function for control of apoptosis, one may anticipate that this problem, too, will be solved in the not-too-distant future. Yet another intriguing problem for which there is presently almost no hard information is whether TGF-p might be cova- lently modified, as by alkylation, acylation, phosphorylation, or prenylation, after it is synthesized on the ribosome. Such covalent modification would allow for a great increase in the regulatory activities of TGF-p, as has been shown elegantly for histones, with the development of the "histone code" (6). Thus, the present volume, rich as it is in abundant and important information, may be regarded not only as an excellent summary of the state of the art in TGF-p research, but also a harbinger of significant exciting new developments to come. Michael B. Sporn, MD Department ofPharmacology, Dartmouth Medical School Hanover, NH REFERENCES 1. Frolik CA, Dart LL, Meyers CA, Smith DM, Sporn MB. Purification and initial characterization of a type- beta transforming growth factor from human placenta. Proc Nat! Acad Sci USA 1983;80:3676-3680. 2. Assoian RK, Komoriya A, Meyers CA, Sporn MB. Transforming growth factor-beta in human platelets: Identification of a major storage site, purification, and characterization. J Biol Chern 1983;258:7155-7160. 3. Roberts AB, Anzano MA, Meyers CA, Wideman J, Blacher R, Pan Y-C E, Stein S, Lehrman SR, Smith JM, Lamb LC, Sporn MB. Purification and properties of a type beta transforming growth factor from bovine kidney. Biochemistry 1983;22:5692-5698. 4. Sporn MB, Roberts AB. TGF-~: Problems and prospects. Cell Regulation 1990; 1:875-882. 5. Sporn MB. The early history of TGF-~, and a brief glimpse of its future. Cytokine Growth Factor Rev 2006;17:3-7. 6. Fischle W, Wang Y, Allis CD. Binary switches and modification cassettes in histone biology and beyond. Nature 2003;425:475-479. PREFACE The transforming growth factor-f (TGF-~) superfamily of secreted signaling proteins shows high conservation among eukaryotes. This superfamily is composed of proteins that regulate cell fate in development and homeostasis including tissue remodeling, histogenesis and maintenance of epithelial homeostasis. TGF-~ was originally named for its ability to induce malignant behavior of normal fibroblasts and it was proposed that TGF-~ might playa role in uncoupling a cell from normal growth control. Paradoxically, TGF-~ exhibits a ubiquitous pattern of expression in normal developing and adult tissues, and unlike most polypeptide growth factors, TGF-~ is produced by, and can act on, nearly every cell type. Numerous studies have established that the TGF-~ signaling mechanism begins with TGF-~ ligand binding to TGF-~ receptors that causes receptor serine/threonine kinases to phosphorylate and activate receptor-regulated Smads, and/or initiate non-Smad signaling through activation of mitogen-activated protein kinases, phosphatidylinositol 3-kinase and other mediators. The receptor-regulated Smads heterooligomerize with the common Smad, Smad4, before translocating to the nucleus, where they regulate gene expression. Mutations and epigenetic dysregulation of TGF-~ signaling mechanisms occur commonly in major human diseases including cancer, fibrosis, and immune and vascular diseases. The TGF-~ signaling system controls a wide range of cellular functions that depend on cell type and physiological or patho-physiological context. In epithelial cells, TGF-~ may play several roles including inhibition of cell growth, initiation of apoptosis and induction of epithelial to mesenchymal transition. In contrast, the effects of TGF-~ on cellular growth and apoptosis in stromal fibroblasts are minor compared with its potent ability to stimulate cell-matrix adhesion and matrix remodeling and promotion of cell motility. Elucidation of cell type- and context-dependent molecular signaling mechanisms that control the varia- tions in functional specificity of TGF-~ signaling is extremely important in understanding key processes that occur in normal development and homeostasis and how these processes change in cancer and disease. With the discovery that TGF-~ is a potent growth inhibitor of epithelial cells and the identification of inactivating mutations within the TGF-~ sig- naling pathway in cancer, it has become clear that the TGF-~ signaling system is a tumor suppressor pathway in early stages of cancer progression. However,many human cancers show increased expression of TGF-~ that is associated with poor patient prognosis and increased frequency of metastasis. The stage-specific duality of multifunctional TGF-~ is the emerging paradigm for the role of TGF-~ in cancer and disease and the mechanism by which the switch of TGF-~ from heroic tumor suppressor to villainous pro-oncogene occurs is the subject of intense investigation. New therapeutic opportunities may emerge from a clearer understanding of the molecular and cellular contexts that permit the tumor suppressor versus oncogenic activities of TGF-~. It has been nearly 25 years since TGF-~ was discovered and several thousand articles have been published about the role of TGF-~ in normal and tumor cells. During the same time, there has been a large increase in our understanding of TGF-~ in cancer and disease. There has also been a significant change in the general direction of therapeutics' discovery and development. Both protein therapeutics and small molecule therapeutics are now described as being molecularly targeted. It is time to review the field of TGF-~ in cancer and cancer therapy in the post-genomic, molecularly targeted era. IX x Preface As part of the Cancer Drug Discovery and Development series, Transforming Growth Factor-jJ in Cancer Therapy attempts to provide an overview of the current status of knowledge about TGF-p in basic and clinical biology and in cancer treatment and therapy. As with other volumes in the series, Transforming Growth Factor-jJ in Cancer Therapy is intended as a resource for both new and experienced investigators who are interested in the fields of polypeptide growth factors, cancer, and human disease, especially since TGF-p regulates and is regulated by a host of growth factors and transcription factors. Persons who are not working directly in the field, but who have a desire to learn about TGF-~ and new approaches for using the TGF-~ signaling pathway components for treatment and therapy in cancer and disease, will also benefit from this book. Each chapter presents a thorough review of the specific subject matter along with current state-of-the-art information by a leading expert in the field. Transforming Growth Factor-jJ in Cancer Therapy is presented in two companion volumes. The aim of Volume I is to provide a compendium of findings about the role of TGF-~ in basic and clinical biology. The book examines in detail basic concepts of TGF-~ signaling in normal physiology and cancer pathobiology that have been elucidated in the past two and a half decades. Volume I begins with a Foreword authored by the elder statesman, Michael B. Sporn, MD, who along with his colleague, Anita B. Roberts, PhD, originally discovered TGF-~ and pioneered studies on its structure, function, expression and signaling. Volume I contains 45 chapters and is divided into three parts. Part I presents basic concepts of TGF-~ signaling in normal physiology and cancer patho- biology including the topics TGF-p in homeostasis, latent TGF-~ and its activation and availability for interaction with latent TGF-p binding proteins in in vitro and in vivo microenvironments, Smad-dependent and Smad-independent pathways in TGF-~ sig- naling, nucleocytoplasmic shuttling mechanisms ofTGF-~, transcriptional regulation of the TGF-~ ligand isoforms, the role of the proteasome in controlling TGF-~ signaling, crosstalk of TGF-B with other regulatory molecules and signaling pathways, TGF-B signaling in epithelial to mesenchymal transition, mechanisms ofTGF-B-induced apop- tosis and cell cycle regulation, interaction of TGF-p with matrix metalloproteinases, and interaction of TGF-p with oncogenes like Ras in mouse models of tumorigenesis and their relation to human cancer. In addition to prototypical TGF-p, Part II explores the role of several other members of the TGF-p superfamily in normal and tumor biology including Mullerian inhibiting substances, growth and differentiation factors, bone morpho- genetic proteins, activins, inhibins, endoglin and Betaig-h3. A proteomics analysis of TGF-~ superfamily members is presented, along with studies of regulation of the TGF-p superfamily by betaglycan and myostatin. Part III examines the importance of TGF-p in inflammation and fibrosis including the roles of triterpenoids, vitamin D, Smads and thrombospondin in TGF-p signaling in the fibrotic response, gene therapy using ultrasound-microbubble-mediated inducible Smad7, negative regulation of signaling by inhibitory Smads, and use ofTGF-p peptide inhibitors and TGF-p antisense oligonu- cleotides for therapy of fibrosis and an overexpressed truncated TGF-p type II receptor that inhibits fibrotic behavior. The aim of companion Volume II of Transforming Growth Factor-fJ in Cancer Therapy is to provide a compendium of findings about the role of TGF-p in cancer treatment and therapy. Volume II begins with a Foreword penned by the elder statesman Carl-Henrik Heldin, PhD, who, along with his pioneering studies on the structure and function of platelet derived growth factor (PDGF) and applications of PDGF to new treatments of cancer, has also conducted seminal studies on mechanisms of TGF-p signaling and its inhibition, and is now applying TGF-p to new regimens for

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Most books are stored in the elastic cloud where traffic is expensive. For this reason, we have a limit on daily download.