Tài liệu Molecular biology of cancer (Lauren Pecorino)

Molecular Biology of Cancer This page intentionally left blank Molecular Biology of Cancer Mechanisms, Targets, and Therapeutics THIRD EDITION Lauren Pecorino University of Greenwich 1 1 Great Clarendon Street, Oxford, OX2 6DP, United Kingdom Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries © Lauren Pecorino 2012 The moral rights of the author have been asserted First Edition copyright 2005 Second Edition copyright 2008 Impression: 1 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, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by licence or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer British Library Cataloguing in Publication Data Data available Library of Congress Cataloging in Publication Data Library of Congress Control Number: 2012932747 ISBN 978–0–19–957717–0 Printed in Italy on acid-free paper by L.E.G.O. S.p.A.—Lavis TN Links to third party websites are provided by Oxford in good faith and for information only. Oxford disclaims any responsibility for the materials contained in any third party website referenced in this work. This book is dedicated to my mentors: Raffaela and Joseph Pecorino Professor Frank Erk Professor Sidney Strickland Professor Jeremy Brockes In memory of: Marie Favia Mildred Maiello Kerry O’Neill This page intentionally left blank ■ P RE FACE Molecular Biology of Cancer: Mechanisms, Targets, and Therapeutics is intended for both undergraduate and graduate-level students (including medical students) and employees in the pharmaceutical industry interested in learning about how a normal cell becomes transformed into a cancer cell. Signaling pathways of a cell detect and respond to changes in the environment and regulate normal cellular activities. Cells contain many receptors on their membrane that allow a signal from outside the cell (e.g. growth factors) to be transmitted to the inside of the cell. Signaling pathways are composed of molecules that interact with other molecules, whereby one triggers the next in a sequence, in a way similar to the actions of team members in a relay race. The relay of information may cause a change in cell behavior or in gene expression, and results in a cellular response (e.g. cell growth). Interference in these signal transduction pathways has grave consequences (e.g. unregulated cell growth) and may lead to the transformation of a normal cell into a cancer cell. The identification of the malfunctions of specific pathways involved in carcinogenesis provides scientists with molecular targets that can be used to generate new cancer therapeutics. I have chosen to present the biology of cancer together with a promise for its application towards designing new cancer drugs. Therefore, for most chapters in the text, the first half discusses the cell and molecular biology of a specific hallmark of cancer and the last half of the chapter discusses therapeutic strategies. To help form a link between particular molecular targets discussed in the first half of the chapter and the therapeutic strategies discussed in the last half of the chapter, a target symbol () is shown in the margin. I hope that this presentation stimulates interest and motivates learning of the subject matter. Several new topics have been added to this third edition. They include: an update on the hallmarks of cancer, chromothripsis, strategies that target DNA repair, microRNAs, and reprogramming energy metabolism. Deservedly, a section on the immune system has been added to the chapter on infection and inflammation and a section on pharmacogenetics has been added to the discussion about the cancer industry in Chapter 12, a chapter that may be valuable for special career interests and supplementary for some cancer courses. The final chapter, “Cancer in the future”, focuses on cancer vaccines and technology. Personally, I believe that the use of diagrams and illustrations is an extremely powerful tool of learning. A picture paints a thousand words . . . and more. I strongly suggest that the reader studies and enjoys the figures, artistically created by Joseph Pecorino. Major points and new cancer viii P R E FAC E therapeutics are illustrated in red, and the target symbol () is used to identify molecular targets. Detailed descriptions of the figures are found in the body of the text. This edition contains the inclusion of additional color plates of experimental data. Several features that are used throughout the text to facilitate learning and interest are described below: Pause and think These features are often presented in the margins of the text and are designed to engage the reader in thought and to present additional perspectives of core concepts. Many times questions are posed; sometimes they are answered and other times they encourage the rereading of particular sections of text. How do we know that? These features examine experimental evidence from the scientific literature and ask the reader to analyze raw data or understand the details of an experimental protocol. Special interest boxes Shaded boxes are used to highlight special topics of interest such as the box entitled “Skin cancer” in Chapter 2. They are also used to provide additional explanation of more complex subjects such as “A little lesson about ROS . . .” in Chapter 2, and “A little lesson about the MAP kinase family . . .” in Chapter 4. Lifestyle tips These are suggestions about lifestyle choices and habits to minimize cancer risk, based on our current knowledge. Leaders in the field of . . . Scientists around the world have made contributions to the concepts presented in this text. Short biographies of several leading scientists, including their major contributions to a particular field of cancer biology, are presented. This feature is meant to give a human touch to the text. It may also be used as a tool for professional use and for following a continuing interest in the research literature. It may be of interest to listen to leading scientists in a particular subject area by attending scientific conferences. PREFACE Analysis of . . . Specific molecular techniques used to analyze particular biological and cellular events are described. It is important that science and medical professionals ask themselves “How do we know that?”. Each of the major concepts underlying our current state of knowledge is the result of numerous experiments that generate data, suggesting possible explanations and mechanisms of cellular events. The information retrieved is governed by the techniques that are used for analysis. Chapter highlights: refresh your memory Summary points are listed in order to consolidate major concepts and provide a brief overview of the chapter. These may be particularly useful for revising for examinations. Self tests and activities Several features are included to strengthen your understanding of particular concepts presented in the chapter: Self tests presented within the text ask you to immediately reinforce material just presented and often refer to a figure. This causes a break from reading and engages you, the student, in “active” learning. Activities that are aimed at strengthening your understanding of particular concepts and encouraging additional self-centered learning are presented towards the end of a chapter. Some require webbased research, while others are more reflective. Multiple choice questions can be found on the companion website. Further reading is a list of general references found at the end of each chapter. These references consist mostly of reviews and support the contents of the chapter. They are not referenced in the main body of the text. Selected special topics mainly lists specific primary research papers that are referenced in the main body of the text and may be pursued for further interest. Several relevant web sites are also included. Appendix 1 is a summary diagram that links key molecular pathways to the cell cycle. Appendix 2 lists centers of cancer research as a starting point for searching for research posts and employment in the field. Entries are separated by location (USA and UK). ix x P R E FAC E Glossary Over 160 entries are defined in a clear and concise manner in order to provide students with a handy reference point for finding explanations of unfamiliar words. It is my hope that the readers of this text will learn something new, become interested in something molecular, and ultimately, somehow, contribute to the field of cancer biology. This field is evolving at a tremendous rate, and so by the time of printing the information contained within these pages will need to be updated! This does not concern me because my aim is to present a process of how the pieces of science are put together and how we may attempt to apply our knowledge to cancer therapies. Many new drugs will fail but a select few will not. These select few will make marked improvements in the quality of life for many. New to this edition • Updates on the hallmarks of cancer and metastasis. • New topics covered, including chromothripsis, the therapeutic potential of gene signatures, microRNAs, and reprogramming energy metabolism. • Additional background information and enhanced explanation of immunology. ■ ACK N O W LEDG M E NTS First, I would like to express my deepest gratitude to Jonathan Crowe, Commissioning Editor, at Oxford University Press (OUP). I am indebted to him for his faith that I could turn a one-page proposal into a complete textbook for the first edition and for his continued support during the writing of the following editions. He nurtured the synthesis of the book with special care, and provided a wealth of helpful suggestions and advice. With love, I thank my father, Joseph Pecorino, for his never-ending encouragement and I acknowledge his artistic talent used to translate dozens of my stick drawings into precise illustrations for the book during our visits across the Atlantic Ocean over the years. Stephen Crumly kindly reproduced the illustrations using his fine skills in computer graphics under tight deadlines. Thanks to Philippa Hendry, Production Editor, and her production staff, and Dewi Jackson and Sarah Broadly for additional assistance at Oxford University Press. I also thank Jayne MacArthur for her careful proofreading of the book. Kind appreciation is expressed for the precise and critical comments given by my official reviewers for the first edition: Tony Bradshaw, Oxford Brookes University, UK; Moira Galway, St Francis Xavier University, Canada; Maria Jackson, University of Glasgow, UK; Helen James, University of East Anglia (UEA), UK; and Ian Judson, Cancer Research UK, London, UK. The value added to the text by these scientists cannot be underestimated. Their comments have had tremendous impact and provided a foundation for the second edition. Special thanks is expressed for the critical comments given by my official reviewers for new chapters of the second edition—Michael Carty, NUI Galway, Irish Republic; from the UK: Joanna Wilson, Glasgow, Jonathan Bard, Edinburgh, Phillipa Darbre, Reading, Stephanie McKeown, Ulster, Penka Nikolova, KCL, Elana Klenova, Essex; from the USA: Annemarie Bettica, Manhattanville College, Nancy Bachman, Oneonta, and James Olesen, Ball State University. Kind appreciation is expressed to my most recent set of reviewers: Roger Barraclough, University of Liverpool; Helen Coley, University of Surrey; Meg Duroux, Aalborg University; Paula M. Checchi, University of California, Davis; Jill Johnston, The University of Sydney; Tapas K. Sengupta, Indian Institute of Science Education and Research (IISER), Kolkata; Paola Marignani, Dalhousie University; Andrew Sharrocks, University of Manchester; and Alicia F. Paulson, University of South Dakota. I thank Rita Canipari, Ken Douglas, Dario Tuccinardi, Ricky Rickles, Anne Schuind, and Sarah Thurston for providing unofficial scientific xii AC KNOW L E DGMEN TS critical comments to previous editions and Dylan Edwards, UEA, Nicole Bournias-Vardiabasis, University of Californa at San Bernadino, and Young-Joon Surh, Seoul National University, for suggestions to previous editions. Many improvements in the third edition are a result of casual feedback from many people from different places—so many thanks to all of you and apologies to those I have not named. I thank my colleagues, Babs Chowdhry, Mark Edwards, John Spencer, and Laurence Harbige for suggestions and communicating cancer news. Special thanks also to the Dean of School, Martin Snowden, for his support of this project. I am thankful for suggestions and literature reviews from former students of the University of Greenwich, Kenny Pratt, and Stephen O’Grady. I acknowledge the financial support of the School of Science, University of Greenwich, and The Biochemical Society to attend the American Association of Cancer Research (AACR) Annual Meetings over the last few years. The information gained and contacts made were important resources for this edition. Appreciation for their kind gestures of support of this textbook is given to Samuel Adunyah, Meharry Medical College; David Axelrod, Rutgers; Michael Caligiuri, Ohio State University; Jules Harris, University of Arizona; and Candace Ritchie, Merck, who I met at these conferences. Many fellow scientists have made suggestions or other contributions to the book, including: Jeremy Griggs, several members of the Kuriyan Laboratory, David Lyden, Weil Cornell Medical College, Gerd Pfeifer, Mariann Rand-Weaver, and Jerry Shay. Special thanks are expressed to Andrea Cossarizza, Sarah Cowan, Xiuhuai Liu, M.-A. Shibata, and Kelly Dobben-Annis for helping me to obtain electronic figures. The Royal Society of Medicine Library, London, provided an ideal scientific sanctuary. I am especially grateful to the support that came from my family, especially Raffaela Pecorino and Teresa Rapillo, and from friends. I am grateful for the tremendous support given by Marcus Gibson. I admire and acknowledge the work of all those scientists whose research efforts have contributed to the field of cancer research. ■ OUTLINE CONTENTS 1 Introduction 2 DNA structure and stability: mutations versus repair 21 3 Regulation of gene expression 53 4 Growth factor signaling and oncogenes 77 5 The cell cycle 103 6 Growth inhibition and tumor suppressor genes 123 7 Apoptosis 149 8 Stem cells and differentiation 173 9 Metastasis 197 10 The immune system, infections, and inflammation 225 11 Nutrients, hormones, and gene interactions 253 12 The cancer industry: drug development, pharmacogenomics, and clinical trial design 283 Cancer in the future: focus on cancer vaccines and technology 299 13 1 APPENDIX 1: CELL CYCLE REGULATION 321 APPENDIX 2: CENTERS FOR CANCER RESEARCH 323 GLOSSARY 327 INDEX 337 This page intentionally left blank ■ DETAILED CONTENTS 1 2 Introduction 1.1 What is cancer? 1.2 Evidence suggests that cancer is a disease of the genome at the cellular level 1.3 Influential factors in human carcinogenesis 10 1.4 Principles of conventional cancer therapies 13 1.5 Clinical trials 15 1.6 The role of molecular targets in cancer therapies 16 DNA structure and stability: mutations versus repair 5 21 22 2.2 Mutations 23 2.3 Carcinogenic agents 25 DNA repair and predispositions to cancer 38  Therapeutic strategies 42 2.5 Conventional therapies: chemotherapy and radiation therapy 42 2.6 Strategies that target DNA repair pathways 47 2.4 4 2 Gene structure—two parts of a gene: the regulatory region and the coding region 2.1 3 1 Regulation of gene expression 53 3.1 Transcription factors and transcriptional regulation 53 3.2 Chromatin structure 59 3.3 Epigenetic regulation of transcription 60 3.4 Evidence of a role for epigenetics in carcinogenesis 63 3.5 Telomeres and telomerase 66 3.6 MicroRNAs (miRNAs) and regulation of mRNA expression 69  Therapeutic strategies 70 3.7 Epigenomic and histonomic drugs 70 3.8 Telomerase inhibitors 72 Growth factor signaling and oncogenes 77 4.1 Epidermal growth factor signaling: an important paradigm 77 4.2 Oncogenes 86 xvi DE TAI L E D C ON TEN TS 4.3 5 6 Kinases as drug targets 95 103 5.1 Cyclins and cyclin-dependent kinases (cdks) 104 5.2 Mechanisms of cdk regulation 107 5.3 Progression through the G1 checkpoint 109 5.4 The G2 checkpoint 111 5.5 The mitotic checkpoint 112 5.6 The cell cycle and cancer 114  Therapeutic strategies 117 5.7 Cyclin-dependent kinase inhibitors 117 5.8 Other cell cycle kinase targets 118 5.9 Inhibitors of the mitotic spindle 118 Growth inhibition and tumor suppressor genes 123 6.1 Definitions of tumor suppressor genes 123 6.2 The retinoblastoma gene 127 6.3 Mutations in the RB pathway and cancer 129 6.4 The p53 pathway 129 6.5 Mutations in the p53 pathway and cancer 137 6.6 Interaction of DNA viral protein products with RB and p53 139  Therapeutic strategies 141 Targeting of the p53 pathway 141 Apoptosis 149 7.1 Molecular mechanisms of apoptosis 150 7.2 Apoptosis and cancer 160 7.3 Apoptosis and chemotherapy 164 7.4 8 95 The cell cycle 6.7 7  Therapeutic strategies  Therapeutic strategies 165 Apoptotic drugs 165 Stem cells and differentiation 173 8.1 Stem cells and cancer 174 8.2 Differentiation and the regulation of transcription 184  Therapeutic strategies 189 8.3 Inhibitors of the Wnt pathway 190 8.4 Inhibitors of the Hh pathway 191 8.5 Leukemia and differentiation therapies 192 DE TAILED CONT E NT S 9 Metastasis 9.1 The process of metastasis 198 9.2 Tools of cell invasion: cell adhesion molecules, integrins, and proteases 199 9.3 Intravasation 203 9.4 Transport 203 9.5 Extravasation 204 9.6 Metastatic colonization 205 9.7 Angiogenesis 206 9.8 Other means of tumor neovascularization 212  Therapeutic strategies 212 Metalloproteinase inhibitors (MPIs) 213 9.9 10 9.10 Strategies for restoring metastasis suppressors 214 9.11 Anti-angiogenic therapy and vascular targeting 214 9.12 Targeting several steps of metastasis at once 220 The immune system, infections, and inflammation 225 10.1 The immune system and cancer 226 10.2 Identifying infectious agents as carcinogens 230 10.3 Inflammation and cancer 237  Therapeutic strategies 11 197 243 10.4 A national vaccination program against hepatitis B virus in Taiwan 244 10.5 Eradication of H. pylori and the relationship to prevention of gastric cancer 244 10.6 Cancer vaccines to prevent cervical cancer 245 10.7 Inhibition of inflammation 246 Nutrients, hormones, and gene interactions 253 11.1 Causative factors 255 11.2 Preventative factors: microconstituents of fruits and vegetables 259 11.3 Reprogramming energy metabolism in tumor cells—an emerging hallmark of cancer 11.4 Genetic polymorphisms and diet 265 268 11.5 Vitamin D: a link between nutrients and hormone action 269 11.6 Hormones and cancer 271  Therapeutic strategies 11.7 “Enhanced” foods and dietary supplements for chemoprevention 274 274 11.8 Drugs that target energy pathways 276 11.9 Drugs that target estrogen 276 xvii xviii DE TAI L E D C ON TEN TS 12 13 The cancer industry: drug development, pharmacogenomics, and clinical trial design 283 12.1 Strategies of drug development 283 12.2 Development of imatinib 287 12.3 Second- and third-generation therapeutics 288 12.4 Pharmacogenomics 290 12.5 Improved clinical trial design 292 12.6 A career in cancer research 295 Cancer in the future: focus on cancer vaccines and technology 299 13.1 Cancer vaccines 300 13.2 Microarrays and gene expression profiling 306 13.3 Diagnostics and prognostics 308 13.4 Imaging 310 13.5 Personalized medicine and bioinformatics 311 13.6 Cancer nanotechnology 313 13.7 Treating cancer symptoms 314 13.8 Are we making progress? 315 APPENDIX 1: CELL CYCLE REGULATION 321 APPENDIX 2: CENTERS FOR CANCER RESEARCH 323 GLOSSARY 327 INDEX 337 Chapter 1 Introduction Introduction The aim of this text is to provide a foundation in the molecular biology of cancer and to demonstrate the conceptual process that is being pursued in order to design more specific cancer drugs. Common threads are woven throughout the different chapters so that the terminology becomes familiar and the mechanisms of cellular processes become clear. The text also provides guidance for everyday decisions that may lead to a decrease in cancer risk. The translation of the knowledge of molecular pathways into clinically important therapies (linked throughout the text by the target symbol, ““) will be communicated and will breathe excitement into learning. Academically, you will gain a foundation in the cell and molecular biology of cancer. More importantly, you will develop an intellectual framework upon which you can add new discoveries that will interest you throughout your lifetime. My goal in writing this book is to inspire. It would be most gratifying for me if, by reading this book, you, the reader, will be compelled to contribute to the cancer research field directly. Knowledge is powerful. Cancer statistics are shocking. One in three people is likely to suffer from cancer during their lifetime. Siegel et al. (2011) estimated that 571, 950 Americans would die from cancer in 2011, and the mortality rate (number of cancer deaths per year per 100 000 people) was over 200 for men in the UK in 2008 (Summary June 2011, Cancer Research, UK). The worldwide incidence (number of new cases) was estimated to be about 12.7 million cases in 2008 (Jemal et al., 2011). These numbers are cold, stark, and impersonal. Hidden behind them are tears, fears, pain, and loss. No one is excluded from the risk. There is a need to understand the disease and to translate our knowledge into effective therapies. In order to understand the process of carcinogenesis, whereby a normal cell is transformed into a cancer cell, we must know the intricacies of cell function and the molecular pathways that underlie it. We must consider the cell in the context of the entire body. We have a lot to learn! However, knowledge of the molecular details in important cellular and biochemical pathways can be applied to a new wave of cancer therapies. What better reward for these efforts?