The Biology Of Cancer Weinberg Pdf Download: A Review of the Key Experiments and Concepts in Modern

In this blog [Download] The Biology of Cancer Weinberg PDF Book. This includes information spreads through the expression of key experiments which give readers a sense of finding and provides insights into the conceptual foundation underlying modern cancer biology.

The Biology Of Cancer Weinberg Pdf Download

Download Zip: https://ssurll.com/2vEKaI

The chapters are meant to be read in the order that they appear, in that each builds on the ideas that have been presented in the chapters before it. The first chapter is a condensed refresher course for undergraduate biology majors and pre-doctoral students; it lays out many of the background concepts that are assumed in the subsequent chapters. The driving force of these two editions has been a belief that modern cancer research represents a conceptually coherent field of science that can be presented as a clear, logical progression.

2. the biology ofCANCER SECOND EDITIONRobert A. Weinberg 3. Thispage intentionally left blank to match pagination of print book 4.the biology ofCANCER SECOND EDITIONRobert A. Weinberg 5. GarlandScience Vice President: Denise Schanck Assistant Editor: AllieBochicchio Production Editor and Layout: EJ Publishing ServicesText Editor: Elizabeth Zayatz Copy Editor: Richard K. MickeyProofreader: Sally Huish Illustrator: Nigel Orme Designer: MatthewMcClements, Blink Studio, Ltd. Permissions Coordinator: BeckyHainz-Baxter Indexer: Bill Johncocks Director of DigitalPublishing: Michael Morales Editorial Assistant: Lamia Harik 2014by Garland Science, Taylor & Francis Group, LLCThis bookcontains information obtained from authentic and highly regardedsources. Every effort has been made to trace copyright holders andto obtain their permission for the use of copyright material.Reprinted material is quoted with permission, and sources areindicated. A wide variety of references are listed. Reasonableefforts have been made to publish reliable data and information,but the author and the publisher cannot assume responsibility forthe validity of all materials or for the consequences of their use.All rights reserved. No part of this book covered by the copyrighthereon may be reproduced or used in any format in any form or byany means graphic, electronic, or mechanical, includingphotocopying, recording, taping, or information storage andretrieval systemswithout permission of the publisher.ISBNs:978-0-8153-4219-9 (hardcover); 978-0-8153-4220-5(softcover).Library of Congress Cataloging-in-Publication DataWeinberg, Robert A. (Robert Allan), 1942The biology of cancer. --Second edition. pages cm Includes bibliographical references. ISBN978-0-8153-4219-9 (hardback) -- ISBN 978-0-8153-4220-5 (pbk.) 1.Cancer--Molecular aspects. 2. Cancer--Genetic aspects. 3. Cancercells. I. Title. RC268.4.W45 2014 616.994--dc23 2013012335Publishedby Garland Science, Taylor & Francis Group, LLC, an informabusiness, 711 Third Avenue, New York, NY 10017, USA, and 3 ParkSquare, Milton Park, Abingdon, OX14 4RN, UK.Printed in the UnitedStates of America 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1Visit ourwebsite at the Author Robert A.Weinberg is a founding member of the Whitehead Institute forBiomedical Research. He is the Daniel K. Ludwig Professor forCancer Research and the American Cancer Society Research Professorat the Massachusetts Institute of Technology (MIT). Dr. Weinberg isan internationally recognized authority on the genetic basis ofhuman cancer and was awarded the U.S. National Medal of Science in1997. Front Cover A micrograph section of a human in situ ductalcarcinoma with -smooth muscle actin stained in pink, cytokeratins 5and 6 in redorange, and cytokeratins 8 and 18 in green. (Courtesyof Werner Bcker and Igor B. Buchwalow of the Institute forHematopathology, Hamburg, Germany.) 6. vDedicationIdedicate thissecond edition, as the first one, to my dear wife, Amy ShulmanWeinberg, who endured long hours of inattention, hearing from merepeatedly the claim that the writing of this edition was almostcomplete, when in fact years of work lay ahead. She deserved muchbetter! With much love. 7. This page intentionally left blank tomatch pagination of print book 8. viiPrefaceCompared with otherareas of biological research, the science of molecular oncology isa recent arrival; its beginning can be traced with some precisionto a milestone discovery in 1975. In that year, the laboratory ofHarold Varmus and J. Michael Bishop in San Francisco, Californiademonstrated that normal cell genomes carry a genethey called it aproto-oncogenethat has the potential, following alteration, toincite cancer. Before that time, we knew essentially nothing aboutthe molecular mechanisms underlying cancer formation; since thattime an abundance of information has accumulated that now revealsin outline and fine detail how normal cells become transformed intotumor cells, and how these neoplastic cells collaborate to formlife-threatening tumors. The scientific literature on cancerpathogenesis has grown explosively and today encompasses millionsof research publications. So much information would seem to be apure blessing. After all, knowing more is always better thanknowing less. In truth, it represents an embarrassment of riches.By now, we seem to know too much, making it difficult toconceptualize cancer research as a single coherent body of sciencerather than a patchwork quilt of discoveries that bear only a vaguerelationship with one another. This book is written in a far morepositive frame of mind, which holds that this patchwork quilt isindeed a manifestation of a body of science that has some simple,underlying principles that unify these diverse discoveries. Cancerresearch is indeed a field with conceptual integrity, much likeother areas of biomedical research and even sciences like physicsand chemistry, and the bewildering diversity of the cancer researchliterature can indeed be understood through these underlyingprinciples. Prior to the pioneering findings of 1975, we knewalmost nothing about the molecular and cellular mechanisms thatcreate tumors. There were some intriguing clues lying around: Weknew that carcinogenic agents often, but not always, operate asmutagens; this suggested that mutant genes are involved in somefashion in programming the abnormal proliferation of cancer cells.We knew that the development of cancer is often a long, protractedprocess. And we knew that individual cancer cells extracted fromtumors behave very differently than their counterparts in normaltissues. Now, almost four decades later, we understand how mutantgenes govern the diverse traits of cancer cells and how the traitsof these individual cells determine the behavior of tumors. Many ofthese advances can be traced to the stunning improvements inexperimental tools. The techniques of genetic analysis, which werequite primitive at the beginning of this period, have advanced tothe stage where we can sequence entire tumor cell genomes inseveral days. (This is in sharp contrast to the state of affairs in1975, when the sequencing of oligonucleotides represented aformidable task!) Given the critical role of genotype indetermining phenotype, we now understand, as least in outline, whycancer cells behave the way that they do. On the one hand, themolecular differences among individual cancers suggest hundreds ofdistinct types of human cancer. On the other, molecular andbiochemical analyses reveal that this bewildering diversity reallymanifests a small number of underlying common biochemical traitsand molecular processes. 9. viii Preface Amusingly, much of thisunification was preordained by decisions made 600 million yearsago. Once the laws and mechanisms of organismic development wereestablished, they governed all that followed, including thebehavior of both normal and neoplastic cells. Modern cancerresearchers continue to benefit from this rigid adherence to thefundamental, evolutionarily conserved rules of life. As is evidentrepeatedly throughout this book, much of what we understand aboutcancer cells, and thus about the disease of cancer, has beenlearned by studying the cells of worms and fruit flies and frogs.These laws and principles are invoked repeatedly to explain thecomplex behaviors of human tumors. By providing context andperspective, they can be used to help us understand all types ofhuman cancer. While these basic principles are now in clear view,critical details continue to elude us. This explains why moderncancer research is still in active ferment, and why new,fascinating discoveries are being reported every month. While theycreate new perspectives, they do not threaten the solidity of theenduring truths, which this book attempts to lay out. Theseprinciples were already apparent seven years ago when the firstedition of this book appeared and, reassuringly, their credibilityhas not been undermined by all that has followed. In part, thisbook has been written as a recruiting pamphlet, as new generationsof researchers are needed to move cancer research forward. They areso important because the lessons about cancers origins, laid outextensively in this book, have not yet been successfully applied tomake major inroads into the prevention and cure of this disease.This represents the major frustration of contemporary cancerresearch: the lessons of disease causation have rarely beenfollowed, as day follows night, by the development of definitivecures. And yes, there are still major questions that remain murkyand poorly resolved. We still do not understand how cancer cellscreate the metastases that are responsible for 90% ofcancer-associated mortality. We understand rather little of therole of the immune system in preventing cancer development. Andwhile we know much about the individual signaling moleculesoperating inside individual human cells, we lack a clearunderstanding of how the complex signaling circuitry formed bythese molecules makes the life-and-death decisions that determinethe fate of individual cells within our body. Those decisionsultimately determine whether or not one of our cells begins thejourney down the long road leading to cancerous proliferation and,finally, to a life-threatening tumor. Contemporary cancer researchhas enriched numerous other areas of modern biomedical research.Consequently, much of what you will learn from this book will beuseful in understanding many aspects of immunology, neurobiology,developmental biology, and a dozen other biomedical researchfields. Enjoy the ride! Robert A. Weinberg Cambridge, MassachusettsMarch 2013 10. ixA Note to the ReaderThe second edition of thisbook is organized, like the first, into 16 chapters of quitedifferent lengths. The conceptual structure that was established inthe first edition still seemed to be highly appropriate for thesecond, and so it was retained. What has changed are the contentsof these chapters: some have changed substantially since theirfirst appearance seven years ago, while otherslargely earlychaptershave changed little. The unchanging nature of the latter isactually reassuring, since these chapters deal with earlyconceptual foundations of current molecular oncology; it would bemost unsettling if these foundational chapters had undergoneradical revision, which would indicate that the earlier edition wasa castle built on sand, with little that could be embraced aswell-established, unchanging certainties. The chapters are meant tobe read in the order that they appear, in that each builds on theideas that have been presented in the chapters before it. The firstchapter is a condensed refresher course for undergraduate biologymajors and pre-doctoral students; it lays out many of thebackground concepts that are assumed in the subsequent chapters.The driving force of these two editions has been a belief thatmodern cancer research represents a conceptually coherent field ofscience that can be presented as a clear, logical progression.Embedded in these discussions is an anticipation that much of thisinformation will one day prove useful in devising novel diagnosticand therapeutic strategies that can be deployed in oncologyclinics. Some experiments are described in detail to indicate thelogic supporting many of these concepts. You will find numerousschematic drawings, often coupled with micrographs, that will helpyou to appreciate how experimental results have been assembled,piece-by-piece, generating the syntheses that underlie molecularoncology. Scattered about the text are Sidebars, which consist ofcommentaries that represent detours from the main thrust of thediscussion. Often these Sidebars contain anecdotes or elaborate onideas presented in the main text. Read them if you are interested,or skip over them if you find them too distracting. They arepresented to provide additional interesta bit of extra seasoning inthe rich stew of ideas that constitutes contemporary research inthis area. The same can be said about the Supplementary Sidebars,which have been relegated to the DVD-ROM that accompanies thisbook. These also elaborate upon topics that are laid out in themain text and are cross-referenced throughout the book. Spaceconstraints dictated that the Supplementary Sidebars could not beincluded in the hardcopy version of the textbook. Throughout themain text you will find extensive cross-references whenever topicsunder discussion have been introduced or described elsewhere. Manyof these have been inserted in the event that you read the chaptersin an order different from their presentation here. Thesecross-references should not provoke you to continually leaf throughother chapters in order to track down cited sections or figures. Ifyou feel that you will benefit from earlier introductions to atopic, use these cross-references; otherwise, ignore them. Eachchapter ends with a forward-looking summary entitled Synopsis andProspects. This section synthesizes the main concepts of thechapter and often addresses 11. xA note to the reader ideas thatremain matters of contention. It also considers where researchmight go in the future. This overview is extended by a list of keyconcepts and a set of questions. Some of the questions aredeliberately challenging and we hope they will provoke you to thinkmore deeply about many of the issues and concepts developed.Finally, most chapters have an extensive list of articles fromresearch journals. These will be useful if you wish to explore aparticular topic in detail. Almost all of the cited references arereview articles, and many contain detailed discussions of varioussubfields of research as well as recent findings. In addition,there are occasional references to older publications that willclarify how certain lines of research developed. Perhaps the mostimportant goal of this book is to enable you to move beyond thetextbook and jump directly into the primary research literature.This explains why some of the text is directed toward teaching theelaborate, specialized vocabulary of the cancer researchliterature, and many of its terms are defined in the glossary.Boldface type has been used throughout to highlight key terms thatyou should understand. Cancer research, like most areas ofcontemporary biomedical research, is plagued by numerousabbreviations and acronyms that pepper the text of many publishedreports. The book provides a key to deciphering this alphabet soupby defining these acronyms. You will find a list of suchabbreviations in the back. Also contained in the book is a newlycompiled List of Key Techniques. This list will assist you inlocating techniques and experimental strategies used incontemporary cancer research. The DVD-ROM that accompanies the bookalso contains a PowerPoint presentation for each chapter, as wellas a companion folder that contains individual JPEG files of thebook images including figures, tables, and micrographs. Inaddition, you will find on this disc a variety of media forstudents and instructors: movies and audio recordings. There is aselection of movies that will aid in understanding some of theprocesses discussed; these movies are referenced on the first pageof the corresponding chapter in a blue box. The movies areavailable in QuickTime and WMV formats, and can be used on acomputer or transferred to a mobile device. The author has alsorecorded mini-lectures on the following topics for students andinstructors: Mutations and the Origin of Cancer, Growth Factors,p53 and Apoptosis, Metastasis, Immunology and Cancer, and CancerTherapies. These are available in MP3 format and, like the movies,are easy to transfer to other devices. These media items, as wellas future media updates, are available to students and instructorsat: On the website, qualifiedinstructors will be able to access a newly created Question Bank.The questions are written to test various levels of understandingwithin each chapter. The instructors website also offers access toinstructional resources from all of the Garland Science textbooks.For access to instructors resources please contact your GarlandScience sales representative or e-mail [email protected] Theposter entitled The Pathways of Human Cancer summarizes many of theintracellular signaling pathways implicated in tumor development.This poster has been produced and updated for the Second Edition byCell Signaling Technology. Because this book describes an area ofresearch in which new and exciting findings are being announced allthe time, some of the details and interpretations presented heremay become outdated (or, equally likely, proven to be wrong) oncethis book is in print. Still, the primary concepts presented herewill remain, as they rest on solid foundations of experimentalresults. The author and the publisher would greatly appreciate yourfeedback. Every effort has been made to minimize errors.Nonetheless, you may find them here and there, and it would be ofgreat benefit if you took the trouble to communicate them. Evenmore importantly, much of the science described herein will requirereinterpretation in coming years as new discoveries are made.Please email us at [email protected] with your suggestions, whichwill be considered for incorporation into future editions.PowerPoint is a registered trademark of the Microsoft Corporationin the United States and/or other countries. 12.xiAcknowledgmentsThe science described in this book is the opus ofa large, highly interactive research community stretching acrossthe globe. Its members have moved forward our understanding ofcancer immeasurably over the past generation. The colleagues listedbelow have helped the author in countless ways, large and small, byproviding sound advice, referring me to critical scientificliterature, analyzing complex and occasionally contentiousscientific issues, and reviewing individual chapters and providingmuch-appreciated critiques. Their scientific expertise and theirinsights into pedagogical clarity have proven to be invaluable.Their help extends and complements the help of an equally largeroster of colleagueswho helped with the preparation of the firstedition. These individuals are representatives of a community,whose members are, virtually without exception, ready and pleasedto provide a helping hand to those who request it. I am mostgrateful to them. Not listed below are the many colleagues whogenerously provided high quality versions of their publishedimages; they are acknowledged through the literature citations inthe figure legends. I would like to thank the following for theirsuggestions in preparing this edition, as well as those who helpedwith the first edition. (Those who helped on this second editionare listed immediately, while those who helped with the firstedition follow.)Second edition Eric Abbate, Janis Abkowitz, JulianAdams, Peter Adams, Gemma Alderton, Lourdes Aleman, Kari Alitalo,C. David Allis, Claudia Andl, Annika Antonsson, Paula Apsell,Steven Artandi, Carlos Arteaga, Avi Ashkenazi, Duncan Baird, AmyBaldwin, Frances Balkwill, Allan Balmain, David Bartel, JosepBaselga, Stephen Baylin, Philip Beachy, Robert Beckman, JrgenBehrens, Roderick Beijersbergen, George Bell, Robert Benezra,Thomas Benjamin, Michael Berger, Arnold Berk, Ren Bernards, RameenBeroukhim, Donald Berry, Timothy Bestor, Mariann Bienz, BrianBierie, Leon Bignold, Walter Birchmeier, Oliver Bischof, JohnBixby, Jenny Black, Elizabeth Blackburn, Maria Blasco, MatthewBlatnik, Gnter Blobel, Julian Blow, Bruce Boman, Gareth Bond,Katherine Borden, Lubor Borsig, Piet Borst, Blaise Bossy, MichaelBotchan, Nancy Boudreau, Henry Bourne, Marina Bousquet, ThomasBrabletz, Barbara Brandhuber, Ulrich Brandt, James Brenton, MartaBriarava, Cathrin Brisken, Jacqueline Bromberg, Myles Brown,Patrick Brown, Thijn Brummelkamp, Ferdinando Bruno, Richard Bucala,Janet Butel, Eliezer Calo, Eleanor Cameron, Ian Campbell, JudithCampbell, Judith Campisi, Lewis Cantley, Yihai Cao, Mario Capecchi,Robert Carlson, Peter Carmeliet, Kermit Carraway, Oriol Casanovas,Tom Cech, Howard Cedar, Ann Chambers, Eric Chang, Mark Chao, IainCheeseman, Herbert Chen, Jen-Tsan Chi, Lewis Chodosh, GerhardChristofori, Inhee Chung, Karen Cichowski, Daniela Cimini, TimClackson, Lena Claesson-Welsh, Michele Clamp, Trevor Clancy,Rachael Clark, Bayard Clarkson, James Cleaver, Don Cleveland, DavidCobrinik, John Coffin, Philip Cohen, Robert Cohen, Michael Cole,Hilary Coller, Kathleen Collins, Duane Compton, John Condeelis,Simon Cook, ChristopherCounter, Sara Courtneidge, Lisa Coussens,Charles Craik, James Darnell, Mark Davis, George Daley, Titia deLange, Pierre De Meyts, Hugues de Th, Rik Derynck, Mark Dewhirst,James DeCaprio, Mark Depristo, Channing Der, Tom DiCesare, JohnDick, Daniel DiMaio, Charles Dimitroff, Nadya Dimitrova, CharlesDinarello, Joseph DiPaolo, Peter Dirks, Vishwa Dixit, LawrenceDonehower, Philip Donoghue, Martin Dorf, David Dornan, Gian PaoloDotto, Steven Dowdy, James Downing, Harry Drabkin, Brian Druker,Crislyn DSouza-Schorey, Eric Duell, Patricia Duffner, MichelDuPage, Robert Duronio, Michael Dyer, Nick Dyson, Connie Eaves,Michael Eck, Mikala Egeblad, Charles Eigenbrot, Steve Elledge,Robert Eisenman, Susan Erster, Manel Esteller, Mark Ewen, PatrickEyers, Doriano Fabbro, Reinhard Fssler, Mark Featherstone, DavidFelser, Karen Ferrante, Soldano Ferrone, Isaiah Fidler, BarbaraFingleton, Zvi Fishelson, Ignacio Flores, Antonio Foji, DavidFoster, A. Raymond Frackelton jr., Herv Wolf Fridman, Peter Friedl,Kenji Fukasawa, Priscilla A. Furth, Vladimir Gabai, Brenda Gallie,Jerome Galon, Sanjiv Sam Gambhir, Levi Garraway, Yan Geng, BruceGelb, Richard Gelber, Frank Gertler, Gad Getz, Edward Giovannucci,Michael Gnant, Sumita Gokhale, Leslie Gold, Alfred Goldberg,Richard Goldsby, Jesus Gomez-Navarro, David Gordon, Eyal Gottlieb,Stephen Grant, Alexander Greenhough, Christoph Kahlert, FlorianGreten, Jay Grisolano, Athur Grollman, Bernd Groner, Wenjun Guo,Piyush Gupta, Daniel Haber, William Hahn, Kevin Haigis, MarciaHaigis, William Hait, Thanos Halazonetis, John Haley, Stephen Hall,Douglas Hanahan, Steven Hanks, J. Marie Hardwick, Iswar Hariharan,Ed Harlow, Masanori Hatakeyama, Georgia Hatzivassiliou, Lin He,Matthias Hebrok, Stephen Hecht, 13. xiiAcknowledgments KristianHelin, Samuel Hellman, Michael Hemann, Linda Hendershot, MeenhardHerlyn, Julian Heuberger, Philip Hinds, Susan Hilsenbeck, MichelleHirsch, Andreas Hochwagen, H. Robert Horvitz, Susan Horwitz, PeterHowley, Ralph Hruban, Peggy Hsu, David Huang, Paul Huang, RobertHuber, Honor Hugo, Tony Hunter, Richard Hynes, Tan Ince, Yoko Irie,Mark Israel, Jean-Pierre Issa, Yoshiaki Ito, Michael Ittmann,Shalev Itzkovitz, Tyler Jacks, Stephen Jackson, Rudolf Jaenisch,Rakesh Jain, Katherine Janeway, Ahmedin Jemal, Harry Jenq, KimJensen, Josef Jiricny, Claudio Joazeiro, Bruce Johnson, CandaceJohnson, David Jones, Peter Jones, Nik Joshi, Johanna Joyce,William Kaelin, Kong Jie Kah, Nada Kalaany, Raghu Kalluri, LawrenceKane, Antoine Karnoub, John Katzenellenbogen, Khandan Keyomarsi,Katherine Janeway, William Kaelin jr., Andrius Kazlauskas, JosephKelleher, Elliott Kieff, Nicole King, Christian Klein, PamelaKlein, Frederick Koerner, Richard Kolesnick, Anthony Komaroff,Konstantinos Konstantopoulos, Jordan Krall, Igor Kramnik, WilhelmKrek, Guido Kroemer, Eve Kruger, Genevieve Kruger, Madhu Kumar,Charlotte Kuperwasser, Thomas Kupper, Bruno Kyewski, Sunil Lakhani,Eric Lander, Lewis Lanier, Peter Lansdorp, David Largaespada,Michael Lawrence, Emma Lees, Jacqueline Lees, Robert Lefkowitz,Mark Lemmon, Stanley Lemon, Arnold Levine, Beth Levine, RonaldLevy, Ephrat LevyLahad, Kate Liddell, Stuart Linn, Marta Lipinski,Joe Lipsick, Edison Liu, David Livingston, Harvey Lodish, LawrenceLoeb, Jay Loeffler, David Louis, Julie-Aurore Losman, Scott Lowe,Haihui Lu, Kunxin Luo, Mathieu Lupien, Li Ma, Elisabeth Mack,Alexander MacKerell jr., Ben Major, Tak Mak, Shiva Malek, ScottManalis, Sridhar Mani, Matthias Mann, Alberto Mantovani, RichardMarais, Jean-Christophe Marine, Sanford Markowitz, RonenMarmorstein, Lawrence Marnett, Chris Marshall, G. Steven Martin,Joan Massagu, Lynn Matrisian, Massimilano Mazzone, SandraMcAllister, Grant McArthur, David McClay, Donald McDonald, DavidGlenn McFadden, Wallace McKeehan, Margaret McLaughlinDrubin,Anthony Means, Ren Medema, Cornelis Melief, Craig Mermel, MarekMichalak, Brian Miller, Nicholas Mitsiades, Sibylle Mittnacht,Holger Moch, Ute Moll, Deborah Morrsion, Aristides Moustakis,Gregory Mundy, Cornelius Murre, Ruth Muschel, Senthil Muthuswamy,Jeffrey Myers, Harikrishna Nakshatri, Inke Nthke, Geoffrey Neale,Ben Neel, Joel Neilson, M. Angela Nieto, Irene Ng, Ingo Nindl,Larry Norton, Roel Nusse, Shuji Ogino, Kenneth Olive, AndreOliveira, Gilbert Omenn, Tamer Onder, Moshe Oren, Barbara Osborne,Liliana Ossowski, David Page, Klaus Pantel, David Panzarella,William Pao, Jongsun Park, Paul Parren, Ramon Parsons, DhavalkumarPatel, Mathias Pawlak, Tony Pawson, Daniel Peeper, Mark Peifer,David Pellman, Tim Perera, Charles Perou, Mary Ellen Perry, ManuelPerucho, Richard Pestell, Julian Peto, Richard Peto, StefanoPiccolo, Jackie Pierce, Eli Pikarsky, Hidde Ploegh, NikolausPfanner, Kristy Pluchino, Heike Pohla, Paul Polakis, MichaelPollak,John Potter, Carol Prives, Lajos Pusztai, Xuebin Qin, PriyamvadaRai, Terence Rabbitts, Anjana Rao, Julia Rastelli, David Raulet,John Rebers, Roger Reddel, Peter Reddien, Danny Reinberg, MichaelRetsky, Jeremy Rich, Andrea Richardson, Tim Richmond, GailRisbridger, Paul Robbins, James Roberts, Leonardo Rodriguez,Veronica Rodriguez, Mark Rolfe, Michael Rosenblatt, DavidRosenthal, Theodora Ross, Yolanda Roth, David Rowitch, BrigitteRoyer-Pokora, Anil Rustgi, David Sabatini, Erik Sahai, Jesse Salk,Leona Samson, Yardena Samuels, Bengt Samuelsson, ChristopherSansam, Richard Santen, Van Savage, Andrew Sharrocks, BrianSchaffhausen, Pepper Schedin, Christina Scheel, Rachel Schiff,Joseph Schlessinger, Ulrich Schopfer, Hubert Schorle, DeborahSchrag, Brenda Schulman, Wolfgang Schulz, Bert Schutte, HansSchreiber, Robert Schreiber, Martin Schwartz, Ralph Scully, JohnSedivy, Helmut Seitz, Manuel Serrano, Jeffrey Settleman, KevinShannon, Phillip Sharp, Norman Sharpless, Jerry Shay, StephenSherwin, Yigong Shi, Tsukasa Shibuye, Ben-Zion Shilo, PiotrSicinski, Daniel Silver, Arun Singh, Michail Sitkovsky, GeorgeSledge, Jr., Mark Sliwkowski, David I. Smith, Eric Snyder, PierreSonveaux, Jean-Charles Soria, Ben Stanger, Sheila Stewart, CharlesStiles, Jayne Stommel, Shannon Stott, Jenny Stow, Michael Stratton,Ravid Straussman, Jonathan Strosberg, Charles Streuli, Herman Suit,Peter Sun, Thomas Sutter, Kathy Svoboda, Alejandro Sweet-Cordero,Mario Sznol, Clifford Tabin, Wai Leong Tam, Hsin-Hsiung Tai, MakotoTaketo, Wai Leong Tam, Filemon Tan, Michael Tangrea, MasaeTatematsu, Steven Teitelbaum, Sabine Tejpar, Adam Telerman,Jennifer Temel, David Tenenbaum, Mine Tezal, Jean Paul Thiery,Craig Thompson, Michael Thun, Thea Tlsty, Rune Toftgrd, NicholasTonks, James Trager, Donald L. Trump, Scott Valastyan, Linda vanAelst, Benoit van den Eynde, Matthew Vander Heiden, Maarten vanLohuizen, Eugene van Scott, Peter Vaupel, Laura vant Veer, GeorgeVassiliou, Inder Verma, Gabriel Victora, Christoph Viebahn,Danijela Vignjevic, Bert Vogelstein, Robert Vonderheide, Daniel vonHoff, Dorien Voskuil, Karen Vousden, Geoffrey Wahl, Lynne Waldman,Herbert Waldmann, Graham Walker, Rongfu Wang, Patricia Watson, BillWeis, Stephen Weiss, Irv Weissman, Danny Welch, H. Gilbert Welch,Zena Werb, Marius Wernig, Bengt Westermark, John Westwick, EileenWhite, Forest White, Max Wicha, Walter Willett, Catherine Wilson,Owen Witte, Alfred Wittinghofer, Norman Wolmark, Sopit Wongkham,Richard Wood, Nicholas Wright, Xu Wu, David Wynford-Thomas, MichaelYaffe, Jing Yang, James Yao, Yosef Yarden, Robert Yauch, Xin Ye,Sam Yoon, Richard Youle, Richard Young, Patrick Zarrinkar, AnnZauber, Jiri Zavadil, Lin Zhang, Alicia Zhou, Ulrike Ziebold, KaiZinn, Johannes Zuber, James Zwiebel.Special thanks to Makoto MarkTaketo of Kyoto University and Richard A. Goldsby of AmherstCollege. 14. Acknowledgments First edition Joan Abbott, Eike-GertAchilles, Jerry Adams, Kari Alitalo, James Allison, David Alpers,Fred Alt, Carl Anderson, Andrew Aprikyan, Jon Aster, Laura Attardi,Frank Austen, Joseph Avruch, Sunil Badve, William Baird, FrancesBalkwill, Allan Balmain, Alan Barge, J. Carl Barrett, David Bartel,Renato Baserga, Richard Bates, Philip Beachy, Camille Bedrosian,Anna Belkina, Robert Benezra, Thomas Benjamin, Yinon Ben-Neriah,Ittai Ben-Porath, Bradford Berk, Ren Bernards, Anton Berns, KennethBerns, Monica Bessler, Neil Bhowmick, Marianne Bienz, Line Bjrge,Harald von Boehmer, Gareth Bond, Thierry Boon, Dorin-Bogdan Borza,Chris Boshoff, Nol Bouck, Thomas Brabletz, Douglas Brash, CathrinBrisken, Garrett Brodeur, Patrick Brown, Richard Bucala, PatriciaBuffler, Tony Burgess, Suzanne Bursaux, Randall Burt, StephenBustin, Janet Butel, Lisa Butterfield, Blake Cady, John Cairns,Judith Campisi, Harvey Cantor, Robert Cardiff, Peter Carroll,Arlindo Castelanho, Bruce Chabner, Ann Chambers, Howard Chang,Andrew Chess, Ann Cheung, Lynda Chin, Francis Chisari, Yunje Cho,Margaret Chou, Karen Cichowski, Michael Clarke, Hans Clevers, BrentCochran, Robert Coffey, John Coffin, Samuel Cohen, Graham Colditz,Kathleen Collins, Dave Comb, John Condeelis, Suzanne Cory,Christopher Counter, Sara Courtneidge, Sandra Cowan-Jacob, JohnCrispino, John Crissman, Carlo Croce, Tim Crook, Christopher Crum,Marcia Cruz-Correa, Gerald Cunha, George Daley, RiccardoDalla-Favera, Alan DAndrea, Chi Dang, Douglas Daniels, JamesDarnell, Jr., Robert Darnell, Galina Deichman, Titia de Lange,Hugues de Th, Chuxia Deng, Edward Dennis, Lucas Dennis, RonaldDePinho, Theodora Devereaux, Tom DiCesare, Jules Dienstag, JohnDiGiovanni, Peter Dirks, Ethan Dmitrovsky, Daniel Donoghue, JohnDoorbar, G. Paolo Dotto, William Dove, Julian Downward, GlennDranoff, Thaddeus Dryja, Raymond DuBois, Nick Duesbery, MichelDuPage, Harold Dvorak, Nicholas Dyson, Michael Eck, Walter Eckhart,Argiris Efstratiadis, Robert Eisenman, Klaus Elenius, StevenElledge, Elissa Epel, John Eppig, Raymond Erikson, James Eshleman,John Essigmann, Gerard Evan, Mark Ewen, Guowei Fang, Juli Feigon,Andrew Feinberg, Stephan Feller, Bruce Fenton, Stephen Fesik,Isaiah Fidler, Gerald Fink, Alain Fischer, Zvi Fishelson, DavidFisher, Richard Fisher, Richard Flavell, Riccardo Fodde, M. JudahFolkman, David Foster, Uta Francke, Emil Frei, Errol Friedberg,Peter Friedl, Stephen Friend, Jonas Frisen, Elaine Fuchs, MargaretFuller, Yuen Kai (Teddy) Fung, Kyle Furge, Amar Gajjar, JosephGall, Donald Ganem, Judy Garber, Frank Gertler, Charlene Gilbert,Richard Gilbertson, Robert Gillies, Doron Ginsberg, EdwardGiovannucci, Inna Gitelman, Steve Goff, Lois Gold, Alfred Goldberg,Mitchell Goldfarb, Richard Goldsby, Joseph Goldstein, SusanneGollin, Mehra Golshan, Todd Golub, Jeffrey Gordon, Michael Gordon,Siamon Gordon, Martin Gorovsky, Arko Gorter, Joe Gray, DouglasGreen, Yoram Groner, John Groopman, Steven Grossman, Wei Gu, DavidGuertin, Piyush Gupta, Barry Gusterson, Daniel Haber, James Haber,William Hahn, Kevin Haigis, Senitiroh Hakomori, Alan Hall, DinaGould Halme, Douglas Hanahan, Philip Hanawalt, Adrian Harris,Curtis Harris, Lyndsay Harris, Stephen Harrison, Kimberly Hartwell,Leland Hartwell, Harald zur Hausen, Carol Heckman, Ruth Heimann,Samuel Hellman, Brian Hemmings, LotharHennighausen, MeenhardHerlyn, Glenn Herrick, Avram Hershko, Douglas Heuman, RichardHodes, Jan Hoeijmakers, Robert Hoffman, Robert Hoover, DavidHopwood, Gabriel Hortobagyi, H. Robert Horvitz, Marshall Horwitz,Alan Houghton, Peter Howley, Robert Huber, Tim Hunt, Tony Hunter,Stephen Hursting, Nancy Hynes, Richard Hynes, Antonio Iavarone, J.Dirk Iglehart, Tan Ince, Max Ingman, Mark Israel, Kurt Isselbacher,Tyler Jacks, Rudolf Jaenisch, Rakesh Jain, Bruce Johnson, DavidJones, Richard Jones, William Kaelin, Jr., Raghu Kalluri, AlexanderKamb, Barton Kamen, Manolis Kamvysselis, Yibin Kang, PhilipKantoff, Paul Kantrowitz, Jan Karlsreder, Michael Kastan, MichaelKauffman, William Kaufmann, Robert Kerbel, Scott Kern, KhandanKeyomarsi, Marc Kirschner, Christoph Klein, George Klein, YoelKloog, Alfred Knudson, Frederick Koerner, Anthony Komaroff, KennethKorach, Alan Korman, Eva Kramarova, Jackie Kraveka, Wilhelm Krek,Charlotte Kuperwasser, James Kyranos, Carole LaBonne, Peter Laird,Sergio Lamprecht, Eric Lander, Laura Landweber, Lewis Lanier,Andrew Lassar, Robert Latek, Lester Lau, Derek Le Roith, Chung Lee,Keng Boon Lee, Richard Lee, Jacqueline Lees, Rudolf Leibel, MarkLemmon, Christoph Lengauer, Jack Lenz, Gabriel Leung, ArnoldLevine, Beth Levine, Jay Levy, Ronald Levy, Fran Lewitter,Frederick Li, Siming Li, Frank Lieberman, Elaine Lin, JoachimLingner, Martin Lipkin, Joe Lipsick, David Livingston, HarveyLodish, Lawrence Loeb, Edward Loechler, Michael Lotze, LawrenceLum, Vicky Lundblad, David MacPherson, Sendurai Mani, AlbertoMantovani, Sandy Markowitz, Larry Marnett, G. Steven Martin, SeamusMartin, Joan Massagu, Patrice Mathevet, Paul Matsudaira, AndreaMcClatchey, Frank McCormick, Patricia McManus, Mark McMenamin, U.Thomas Meier, Matthew Meyerson, George Miller, Nathan Miselis,Randall Moon, David Morgan, Rebecca Morris, Simon Conway Morris,Robert Moschel, Bernard Moss, Paul Mueller, Anja Mueller-Homey,William A. Muller, Gregory Mundy, Karl Mnger, Lance Munn, RuthMuschel, Lee Nadler, David G. Nathan, Jeremy Nathans, SergeiNedospasov, Benjamin Neel, David Neuhaus, Donald Newmeyer, LeonardNorkin, Lloyd Old, Kenneth Olive, Tamer Onder, Moshe Oren, TerryOrr-Weaver, Barbara Osborne, Michele Pagano, David Page, AsitParikh, Chris Parker, William Paul, Amanda Paulovich, Tony Pawson,Mark Peifer, David Pellman, David Phillips, Jacqueline Pierce,Malcolm Pike, John Pintar, Maricarmen Planas-Silva, Roland Pochet,Daniel Podolsky, Beatriz Pogo, Roberto Polakiewicz, JeffreyPollard, Nicolae Popescu, Christoph Poremba, Richmond Prehn, CarolPrives, Vito Quaranta, Peter Rabinovitch, Al Rabson, PriyamvadaRai, Klaus Rajewsky, Sridhar Ramaswamy, Anapoorni Rangarajan,Jeffrey Ravetch, Ilaria Rebay, John Reed, Steven Reed, Alan Rein,Ee Chee Ren, Elizabeth Repasky, Jeremy Rich, Andrea Richardson,Dave Richardson, Darrell Rigel, James Roberts, Diane Rodi, CliffordRosen, Jeffrey Rosen, Neal Rosen, Naomi Rosenberg, MichaelRosenblatt, Theodora Ross, Martine Roussel, Steve Rozen, JeffreyRuben, Jos Russo, David Sabatini, Julien Sage, Ronit Sarid, EdwardSausville, Charles Sawyers, David Scadden, David Schatz, ChristinaScheel, Joseph Schlessinger, Anja Schmidt, Stuart Schnitt, RobertSchoen, Robert Schreiber, Edward Scolnick, Ralph Scully, Haroldxiii15. xiv Acknowledgments Seifried, William Sessa, Jeffrey Settleman,Fergus Shanahan, Jerry Shay, James Sherley, Charles Sherr, EthanShevach, Chiaho Shih, Frank Sicheri, Peter Sicinski, Sandy Simon,Dinah Singer, Arthur Skarin, Jonathan Skipper, Judy Small, GilbertSmith, Lauren Sompayrac, Holger Sondermann, Gail Sonenshein,Deborah Spector, Michael Sporn, Eric Stanbridge, E. RichardStanley, Louis Staudt, Philipp Steiner, Ralph Steinman, GuntherStent, Sheila Stewart, Charles Stiles, Jonathan Stoye, MichaelStratton, Bill Sugden, Takashi Sugimura, John Sullivan, NevinSummers, Calum Sutherland, Clifford Tabin, John Tainer, JussiTaipale, Shinichiro Takahashi, Martin Tallman, Steven Tannenbaum,Susan Taylor, Margaret Tempero, Masaaki Terada, Satvir Tevethia,Jean Paul Thiery, William Thilly, David ThorleyLawson, JayTischfield, Robertus Tollenaar, Stephen Tomlinson, DimitriosTrichopoulos, Elaine Trujillo, James Umen, Alex van der Eb, Wim vanEgmond, Diana van Heemst, Laura vant Veer, Harold Varmus, AlexanderVarshavsky, Anna Velcich, Ashok Venkitaraman, Bjrn Vennstrm, InderVerma, Shelia Violette, Bert Vogelstein, Peter Vogt, Olga Volpert,Evan Vosburgh, Geoffrey Wahl, Graham Walker, Gernot Walter, JackWands, Elizabeth Ward, Jonathan Warner, Randolph Watnick, I.Bernard Weinstein, Robin Weiss, Irving Weissman, Danny Welch, H.Gilbert Welch, Zena Werb, Forest White, Michael White, RaymondWhite, Max Wicha, Walter Willet, Owen Witte, Richard Wood, AndrewWyllie, John Wysolmerski, Michael Yaffe, Yukiko Yamashita, GeorgeYancopoulos, Jing Yang, Moshe Yaniv, Chun-Nan Yeh, Richard Youle,Richard Young, Stuart Yuspa, Claudio Zanon, David Zaridze, PatrickZarrinkar, Bruce Zetter, Drazen Zimonjic, Leonard Zon, Weiping ZouReaders: Through their careful reading of the text, these graduatestudents provided extraordinarily useful feedback in improving manysections of this book and in clarifying sections that were, intheir original versions, poorly written and confusing. JamieWeyandt (Duke University), Matthew Crowe (Duke University), VeniceCalinisan Chiueh (University of California, Berkeley), YvetteSoignier (University of California, Berkeley) Question Bank: JamieWeyandt also produced the accompanying question bank available toqualified adopters on the instructor resource site. WhiteheadInstitute/MIT: Christine Hickey was responsible over several yearstime in helping to organize the extensive files that constitutedeach chapter. Her help was truly extraordinary. Dave Richardson ofthe Whitehead Institute library helped on countless occasions toretrieve papers from obscure corners of the vast scientificliterature, doing so with lightning speed! Garland: While this bookhas a single recognized author, it really is the work of manyhands. The prose was edited by Elizabeth Zayatz and Richard K.Mickey, two editors who are nothing less than superb. To the extentthat this book is clear and readable, much of this is a reflectionof their dedication to clarity, precision of language, gracefulsyntax, and the useof images that truly serve to enlighten ratherthan confound. I have been most fortunate to have two suchextraordinary people looking over my shoulder at every step of thewriting process. And, to be sure, I have learned much from them. Icannot praise them enough! Many of the figures are the work ofNigel Orme, an illustrator of great talent, whose sense of designand dedication to precision and detail are, once again, nothingless than extraordinary. Garland Science determined the structureand design and provided unfaltering support and encouragementthrough every step of the process that was required to bring thisproject to fruition. Denise Schanck gave guidance and cheered me onevery step of the way. Unfailingly gracious, she is, in everysense, a superb publisher, whose instincts for design and standardsof quality publishing are a model. All textbook authors should beas fortunate as I have been to have someone of her qualities at thehelm! The editorial and logistical support required to organize andassemble a book of this complexity was provided first by JaneteScobie and then over a longer period by Allie Bochicchio, both ofwhom are multitalented and exemplars of ever-cheerful competence,thoroughness, and helpfulness. Without the organizational skills ofthese two in the Garland office, this text would have emerged as anincoherent jumble. The truly Herculean task of procuringpermissions for publication of the myriad figures fell on theshoulders of Becky Hainz-Baxter. This remains a daunting task, evenin this age of Internet and email. Without her help, it would havebeen impossible to share with the reader many of the images thathave created the field of modern cancer research. The layout is atribute to the talents of Emma Jeffcock, once again an exemplar ofcompetence, who has an unerring instinct for how to make images andthe pages that hold them accessible and welcoming to the reader;she also provided much-valued editorial help that resulted in manyimprovements of the prose. The electronic media associated withthis book are the work of Michael Morales, whose ability toorganize clear and effective visual presentations are indicated bythe electronic files that are carried in the accompanying DVD-ROM.He and his editorial assistant, Lamia Harik, are recognized andthanked for their dedication to detail, thoroughness, and theirgreat talent in providing accessible images that inform the readerand complement the written text. Additional, highly valuable inputinto the organization and design were provided by Adam Sendroff,Alain Mentha, and Lucy Brodie. Together, the Garland team, as citedabove, represents a unique collection of gifted people whoserespective talents are truly peerless and, to say so a second time,individuals who are unfailingly gracious and helpful. Othertextbook authors should be as fortunate as I have been in receivingthe support that I have enjoyed in the preparation of this secondedition! 16. xvContentsChapter 1: The Biology and Genetics of Cellsand Organisms1Chapter 2: The Nature of Cancer31Chapter 3: TumorViruses71Chapter 4: Cellular Oncogenes Chapter 5:Growth Factors,Receptors, and Cancer103 131Chapter 6: Cytoplasmic SignalingCircuitry Programs Many of the Traits of Cancer175Chapter 7:TumorSuppressor Genes231Chapter 8:pRb and Control of the Cell CycleClock275Chapter 9:p53 and Apoptosis: Master Guardian andExecutioner331Chapter 10: Eternal Life: Cell Immortalization andTumorigenesis391Chapter 11: Multi-Step Tumorigenesis439Chapter 12:Maintenance of Genomic Integrity and the Development ofCancer511Chapter 13: Dialogue Replaces Monologue: HeterotypicInteractions and the Biology of Angiogenesis577Chapter 14: MovingOut: Invasion and Metastasis641Chapter 15: Crowd Control: TumorImmunology and Immunotherapy723Chapter 16: The Rational Treatmentof Cancer797AbbreviationsA:1GlossaryG:1IndexI:1 17. xviList of KeyTechniquesApoptotic cells: Various detection techniques (Figure9.19) Apoptotic cells: Detection by the TUNEL assay (SupplementarySidebar 9.2 Chromatin immunoprecipitation (Supplementary Sidebar8.3))Circulating tumor cells: Detection using microfluidic devices(Supplementary Sidebar 14.3 Comparative genomic hybridization (CGH)(Supplementary Sidebar 11.4))DNA sequence polymorphisms: Detectionby polymerase chain reaction (Supplementary Sidebar 7.3 Embryonicstem cells: Derivation of pluripotent mouse cell lines(Supplementary Sidebar 8.1 Fluorescence-activated cell sorting(FACS) (Supplementary Sidebar 11.1 Gene cloning strategies(Supplementary Sidebar 1.5))))Gene cloning: Isolation of genesencoding melanoma antigens (Supplementary Sidebar 15.11)Genecloning: Isolation of transfected human oncogenes (Figure 4.7) Geneknock-in and knock-out: Homologous recombination with mousegerm-line genes (Supplementary Sidebar 7.7 Histopathologicalstaining techniques (Supplementary Sidebar 2.1)Knocking down geneexpression with shRNAs and siRNAs (Supplementary Sidebar 1.4Laser-capture microdissection (Supplementary Sidebar 13.5))Mappingof DNA methylation sites: Use of sequence-specific polymerase chainreaction (Supplementary Sidebar 7.4 Mapping of anoncogene-activating mutation (Figure 4.8) Mapping of tumorsuppressor genes via restriction fragment length polymorphisms(Figure 7.13) Monoclonal antibodies (Supplementary Sidebar11.1)Mutagenicity measurement: The Ames test (Figure 2.27) Probeconstruction: The src-specific DNA probe (Figure 3.20) Reproductivecloning (Supplementary Sidebar 1.2)Retroviral vector construction(Supplementary Sidebar 3.3)Screening for mutant oncoproteins(Figure 16.25) Skin carcinoma induction in mice (Figure 11.30)Southern and Northern blotting (Supplementary Sidebar4.3)Telomerase activity measurements: The TRAP assay (SupplementarySidebar 10.1 Transfection of DNA (Figure 4.1) Transgenic mice:Creating tumor-prone strains (Figure 9.23A) Can be found on theDVD-ROM accompanying the book.))) 18. xviiDetailed ContentsChapter1: The Biology and Genetics of Cells and Organisms 1.1 1.21.31Mendel establishes the basic rules of genetics 2 Mendeliangenetics helps to explain Darwinian evolution 4 Mendelian geneticsgoverns how both genes and chromosomes behave 7 1.4 Chromosomes arealtered in most types of cancer cells 10 Mutations causing canceroccur in both the 1.5 germ line and the soma 11 Genotype embodiedin DNA sequences creates 1.6 phenotype through proteins 14 1.7 Geneexpression patterns also control phenotype 19 Histone modificationand transcription factors control 1.8 gene expression 21 Heritablegene expression is controlled through 1.9 additional mechanisms 241.10 Unconventional RNA molecules also affect the 25 expression ofgenes 1.11 Metazoa are formed from components conserved over vastevolutionary time periods 27 1.12 Gene cloning techniquesrevolutionized the study of normal and malignant cells 28 29Additional readingChapter 2: The Nature of Cancer 2.1 2.2Tumorsarise from normal tissues Tumors arise from many specialized celltypes throughout the body 2.3 Some types of tumors do not fit intothe major classifications 2.4 Cancers seem to develop progressively2.5 Tumors are monoclonal growths 2.6 Cancer cells exhibit analtered energy metabolism 2.7 Cancers occur with vastly differentfrequencies in different human populations 2.8 The risks of cancersoften seem to be increased by assignable influences includinglifestyle 2.9 Specific chemical agents can induce cancer 2.10 Bothphysical and chemical carcinogens act as mutagens 2.11 Mutagens maybe responsible for some human cancers 2.12 Synopsis and prospectsKey concepts Thought questions Additional readingChapter 3: TumorViruses 3.1 3.23.3 3.4Peyton Rous discovers a chicken sarcoma virusRous sarcoma virus is discovered to transform infected cells inculture The continued presence of RSV is needed to maintaintransformation Viruses containing DNA molecules are also able toinduce cancer3132 34 40 45 50 53 55 58 59 60 64 66 68 69 697172 7577 79Tumor viruses induce multiple changes in cell phenotypeincluding acquisition of tumorigenicity 82 3.6 Tumor virus genomespersist in virus-transformed cells by becoming part of host-cellDNA 83 3.7 Retroviral genomes become integrated into thechromosomes of infected cells 87 3.8 A version of the src genecarried by RSV is also present in uninfected cells 89 3.9 RSVexploits a kidnapped cellular gene to transform cells 91 3.10 Thevertebrate genome carries a large group of protooncogenes 93 3.11Slowly transforming retroviruses activate protooncogenes byinserting their genomes adjacent to these cellular genes 94 3.12Some retroviruses naturally carry oncogenes 97 99 3.13 Synopsis andprospects Key concepts 101 Thought questions 102 102 Additionalreading3.5Chapter 4: Cellular Oncogenes 4.1Can cancers be triggeredby the activation of endogenous retroviruses? Transfection of DNAprovides a strategy for detecting 4.2 nonviral oncogenes 4.3Oncogenes discovered in human tumor cell lines are related to thosecarried by transforming retroviruses 4.4 Proto-oncogenes can beactivated by genetic changes affecting either protein expression orstructure 4.5 Variations on a theme: the myc oncogene can arise viaat least three additional distinct mechanisms 4.6 A diverse arrayof structural changes in proteins can also lead to oncogeneactivation 4.7 Synopsis and prospects Key concepts Thoughtquestions Additional readingChapter 5: Growth Factors, Receptors,and Cancer 5.1 5.2 5.3 5.45.5 5.6 5.7 5.8 5.9 103 104 105 108 113117 124 127 128 130 130131Normal metazoan cells control each otherslives 133 The Src protein functions as a tyrosine kinase 135 TheEGF receptor functions as a tyrosine kinase 138 An altered growthfactor receptor can function as an oncoprotein 141 A growth factorgene can become an oncogene: the case of sis 144Transphosphorylation underlies the operations of receptor tyrosinekinases 146 Yet other types of receptors enable mammalian cells tocommunicate with their environment 153 Nuclear receptors sense thepresence of lowmolecular weight lipophilic ligands 159 Integrinreceptors sense association between the cell and the extracellularmatrix 161 19. xviii Detailed contents 5.10 The Ras protein, anapparent component of the downstream signaling cascade, functionsas a G protein 165 5.11 Synopsis and prospects 169 Key concepts 172Thought questions 174 174 Additional readingChapter 6: CytoplasmicSignaling Circuitry Programs Many of the Traits of Cancer 6.1 6.26.3 6.4 6.5A signaling pathway reaches from the cell surface intothe nucleus The Ras protein stands in the middle of a complexsignaling cascade Tyrosine phosphorylation controls the locationand thereby the actions of many cytoplasmic signaling proteins SH2and SH3 groups explain how growth factor receptors activate Ras andacquire signaling specificity Ras-regulated signaling pathways: Acascade of kinases forms one of three important signaling pathwaysdownstream of Ras 6.6 Ras-regulated signaling pathways: a seconddownstream pathway controls inositol lipids and the Akt/PKB kinase6.7 Ras-regulated signaling pathways: a third downstream pathwayacts through Ral, a distant cousin of Ras 6.8 The JakSTAT pathwayallows signals to be transmitted from the plasma membrane directlyto the nucleus 6.9 Cell adhesion receptors emit signals thatconverge with those released by growth factor receptors 6.10 TheWnt-catenin pathway contributes to cell proliferation 6.11G-proteincoupled receptors can also drive normal and neoplasticproliferation 6.12 Four additional dual-address signaling pathwayscontribute in various ways to normal and neoplastic proliferation6.13 Well-designed signaling circuits require both negative andpositive feedback controls 6.14 Synopsis and prospects Key conceptsThought questions Additional readingChapter 7: Tumor SuppressorGenes 7.1 7.2 7.3 7.47.5 7.6 7.7 7.8 7.9 7.10Cell fusionexperiments indicate that the cancer phenotype is recessive Therecessive nature of the cancer cell phenotype requires a geneticexplanation The retinoblastoma tumor provides a solution to thegenetic puzzle of tumor suppressor genes Incipient cancer cellsinvent ways to eliminate wildtype copies of tumor suppressor genesThe Rb gene often undergoes loss of heterozygosity in tumorsLoss-of-heterozygosity events can be used to find tumor suppressorgenes Many familial cancers can be explained by inheritance ofmutant tumor suppressor genes Promoter methylation represents animportant mechanism for inactivating tumor suppressor genes Tumorsuppressor genes and proteins function in diverse ways The NF1protein acts as a negative regulator of Ras signaling175 177 180182 188 189 193 201 202 204 206 209 212 216 217 227 228 228231 232234 235 238 241 243 248 249 254 2557.11 7.12Apc facilitates egressof cells from colonic crypts Von HippelLindau disease: pVHLmodulates the hypoxic response 7.13 Synopsis and prospects Keyconcepts Thought questions Additional reading259Chapter 8: pRb andControl of the Cell Cycle Clock2758.1Cell growth and division iscoordinated by a complex array of regulators 8.2 Cells makedecisions about growth and quiescence during a specific period inthe G1 phase 8.3 Cyclins and cyclin-dependent kinases constitutethe core components of the cell cycle clock 8.4 CyclinCDK complexesare also regulated by CDK inhibitors 8.5 Viral oncoproteins revealhow pRb blocks advance through the cell cycle 8.6 pRb is deployedby the cell cycle clock to serve as a guardian of therestriction-point gate 8.7 E2F transcription factors enable pRb toimplement growth-versus-quiescence decisions 8.8 A variety ofmitogenic signaling pathways control the phosphorylation state ofpRb 8.9 The Myc protein governs decisions to proliferate ordifferentiate 8.10 TGF- prevents phosphorylation of pRb and therebyblocks cell cycle progression 8.11 pRb function and the controls ofdifferentiation are closely linked 8.12 Control of pRb function isperturbed in most if not all human cancers 8.13 Synopsis andprospects Key concepts Thought questions Additional readingChapter9: p53 and Apoptosis: Master Guardian and Executioner 9.1 9.29.39.4 9.5 9.6 9.7 9.8 9.9 9.10 9.11 9.12 9.13 9.14 9.159.16Papovaviruses lead to the discovery of p53 p53 is discovered tobe a tumor suppressor gene Mutant versions of p53 interfere withnormal p53 function p53 protein molecules usually have shortlifetimes A variety of signals cause p53 induction DNA damage andderegulated growth signals cause p53 stabilization Mdm2 destroysits own creator ARF and p53-mediated apoptosis protect againstcancer by monitoring intracellular signaling p53 functions as atranscription factor that halts cell cycle advance in response toDNA damage and attempts to aid in the repair process p53 oftenushers in the apoptotic death program p53 inactivation providesadvantage to incipient cancer cells at a number of steps in tumorprogression Inherited mutant alleles affecting the p53 pathwaypredispose one to a variety of tumors Apoptosis is a complexprogram that often depends on mitochondria Both intrinsic andextrinsic apoptotic programs can lead to cell death Cancer cellsinvent numerous ways to inactivate some or all of the apoptoticmachinery Necrosis and autophagy: two additional forks in the roadof tumor progression265 268 272 273 273276 281 283 288 294 298 299304 306 311 314 318 323 327 328 329331332 334 335 338 339 341 342348 352 355 359 360 361 371 376 379 20. Detailed contents 9.17Synopsis and prospects Key concepts Thought questions Additionalreading381 387 388 389Chapter 10: Eternal Life: CellImmortalization and Tumorigenesis39110.1Normal cell populationsregister the number of cell generations separating them from theirancestors in the early embryo 392 10.2 Cancer cells need to becomeimmortal in order to form tumors 394 10.3 Cell-physiologic stressesimpose a limitation on replication 398 10.4 The proliferation ofcultured cells is also limited by the telomeres of theirchromosomes 404 10.5 Telomeres are complex molecular structuresthat are not easily replicated 409 10.6 Incipient cancer cells canescape crisis by expressing 412 telomerase 10.7 Telomerase plays akey role in the proliferation of 417 human cancer cells 10.8 Someimmortalized cells can maintain telomeres 419 without telomerase10.9 Telomeres play different roles in the cells of laboratory 423mice and in human cells 10.10 Telomerase-negative mice show bothdecreased and 425 increased cancer susceptibility 10.11 Themechanisms underlying cancer pathogenesis in telomerase-negativemice may also operate during the 429 development of human tumors10.12 Synopsis and prospects 433 436 Key concepts Thought questions437 Additional reading 437Chapter 11: Multi-Step Tumorigenesis11.111.2 11.3 11.4 11.5 11.6 11.7 11.8 11.9 11.10 11.11 11.12 11.1311.14439Most human cancers develop over many decades of 440 timeHistopathology provides evidence of multi-step tumor 442 formationCells accumulate genetic and epigenetic alterations as tumorprogression proceeds 449 Multi-step tumor progression helps toexplain familial polyposis and field cancerization 453 Cancerdevelopment seems to follow the rules of Darwinian evolution 455Tumor stem cells further complicate the Darwinian model of clonalsuccession and tumor progression 458 A linear path of clonalsuccession oversimplifies the reality of cancer: intra-tumorheterogeneity 463 The Darwinian model of tumor development isdifficult to validate experimentally 467 Multiple lines of evidencereveal that normal cells are resistant to transformation by asingle mutated gene 468 Transformation usually requirescollaboration between two or more mutant genes 470 Transgenic miceprovide models of oncogene collaboration and multi-step celltransformation 474 Human cells are constructed to be highlyresistant to immortalization and transformation 475 Nonmutagenicagents, including those favoring cell proliferation, make importantcontributions to tumorigenesis 480 Toxic and mitogenic agents canact as human tumor promoters 48411.15 Chronic inflammation oftenserves to promote tumor progression in mice and humans 486 11.16Inflammation-dependent tumor promotion operates 490 through definedsignaling pathways 11.17 Tumor promotion is likely to be a criticaldeterminant of the rate of tumor progression in many human tissues498 11.18 Synopsis and prospects 501 506 Key concepts Thoughtquestions 507 Additional reading 508Chapter 12: Maintenance ofGenomic Integrity and the Development of Cancer 511 12.1Tissues areorganized to minimize the progressive accumulation of mutations12.2 Stem cells may or may not be targets of the mutagenesis thatleads to cancer 12.3 Apoptosis, drug pumps, and DNA replicationmechanisms offer tissues a way to minimize the accumulation ofmutant stem cells 12.4 Cell genomes are threatened by errors madeduring DNA replication 12.5 Cell genomes are under constant attackfrom endogenous biochemical processes 12.6 Cell genomes are underoccasional attack from exogenous mutagens and their metabolites12.7 Cells deploy a variety of defenses to protect DNA moleculesfrom attack by mutagens 12.8 Repair enzymes fix DNA that has beenaltered by mutagens 12.9 Inherited defects in nucleotide-excisionrepair, base-excision repair, and mismatch repair lead to specificcancer susceptibility syndromes 12.10 A variety of other DNA repairdefects confer increased cancer susceptibility through poorlyunderstood mechanisms 12.11 The karyotype of cancer cells is oftenchanged through alterations in chromosome structure 12.12 Thekaryotype of cancer cells is often changed through alterations inchromosome number 12.13 Synopsis and prospects Key concepts Thoughtquestions Additional reading512 515 517 519 523 527 535 538 544 549555 558 564 572 573 574Chapter 13 Dialogue Replaces Monologue:Heterotypic Interactions and the Biology of Angiogenesis 57713.1Normal and neoplastic epithelial tissues are formed frominterdependent cell types 13.2 The cells forming cancer cell linesdevelop without heterotypic interactions and deviate from thebehavior of cells within human tumors 13.3 Tumors resemble woundedtissues that do not heal 13.4 Experiments directly demonstrate thatstromal cells are active contributors to tumorigenesis 13.5Macrophages and myeloid cells play important roles in activatingthe tumor-associated stroma 13.6 Endothelial cells and the vesselsthat they form ensure tumors adequate access to the circulation13.7 Tripping the angiogenic switch is essential for tumorexpansion 13.8 The angiogenic switch initiates a highly complexprocess 13.9 Angiogenesis is normally suppressed by physiologicinhibitors 13.10 Anti-angiogenesis therapies can be employed totreat cancer579 585 587 600 604 607 615 619 622 626xix 21.xxDetailed contents 13.11 Synopsis and prospects Key conceptsThought questions Additional reading634 638 639 639Chapter 14:Moving Out: Invasion and Metastasis64114.1Travel of cancer cellsfrom a primary tumor to a site of potential metastasis depends on aseries of complex biological steps 14.2 Colonization represents themost complex and challenging step of the invasionmetastasis cascade14.3 The epithelialmesenchymal transition and associated loss ofE-cadherin expression enable carcinoma cells to become invasive14.4 Epithelialmesenchymal transitions are often induced bycontextual signals 14.5 Stromal cells contribute to the inductionof invasiveness 14.6 EMTs are programmed by transcription factorsthat orchestrate key steps of embryogenesis 14.7 EMT-inducingtranscription factors also enable entrance into the stem cell state14.8 EMT-inducing TFs help drive malignant progression 14.9Extracellular proteases play key roles in invasiveness 14.10 SmallRas-like GTPases control cellular processes such as adhesion, cellshape, and cell motility 14.11 Metastasizing cells can uselymphatic vessels to disperse from the primary tumor 14.12 Avariety of factors govern the organ sites in which disseminatedcancer cells form metastases 14.13 Metastasis to bone requires thesubversion of osteoblasts and osteoclasts 14.14 Metastasissuppressor genes contribute to regulating the metastatic phenotype14.15 Occult micrometastases threaten the long-term survival ofcancer patients 14.16 Synopsis and prospects Key concepts Thoughtquestions Additional readingChapter 15: Crowd Control: TumorImmunology and Immunotherapy 15.1The immune system functions todestroy foreign invaders and abnormal cells in the bodys tissues15.2 The adaptive immune response leads to antibody production 15.3Another adaptive immune response leads to the formation ofcytotoxic cells 15.4 The innate immune response does not requireprior sensitization 15.5 The need to distinguish self from non-selfresults in immune tolerance 15.6 Regulatory T cells are able tosuppress major components of the adaptive immune response 15.7 Theimmunosurveillance theory is born and then suffers major setbacks15.8 Use of genetically altered mice leads to a resurrection of theimmunosurveillance theory 15.9 The human immune system plays acritical role in warding off various types of human cancer 15.10Subtle differences between normal and neoplastic tissues may allowthe immune system to distinguish between them 15.11 Tumortransplantation antigens often provoke potent immune responses15.12 Tumor-associated transplantation antigens may also evokeanti-tumor immunity643 652 657 662 669 672 677 680 685 689 695 699703 709 711 713 719 720 721723 724 726 729 736 736 737 739 742 745751 756 75815.13 Cancer cells can evade immune detection bysuppressing cell-surface display of tumor antigens 15.14 Cancercells protect themselves from destruction by NK cells andmacrophages 15.15 Tumor cells launch counterattacks on immunocytes15.16 Cancer cells become intrinsically resistant to various formsof killing used by the immune system 15.17 Cancer cells attractregulatory T cells to fend off attacks by other lymphocytes 15.18Passive immunization with monoclonal antibodies can be used to killbreast cancer cells 15.19 Passive immunization with antibody canalso be used to treat B-cell tumors 15.20 Transfer of foreignimmunocytes can lead to cures of certain hematopoietic malignancies15.21 Patients immune systems can be mobilized to attack theirtumors 15.22 Synopsis and prospects Key concepts Thought questionsAdditional readingChapter 16: The Rational Treatment of Cancer16.1The development and clinical use of effective therapies willdepend on accurate diagnosis of disease 16.2 Surgery, radiotherapy,and chemotherapy are the major pillars on which current cancertherapies rest 16.3 Differentiation, apoptosis, and cell cyclecheckpoints can be exploited to kill cancer cells 16.4 Functionalconsiderations dictate that only a subset of the defective proteinsin cancer cells are attractive targets for drug development 16.5The biochemistry of proteins also determines whether they areattractive targets for intervention 16.6 Pharmaceutical chemistscan generate and explore the biochemical properties of a wide arrayof potential drugs 16.7 Drug candidates must be tested on cellmodels as an initial measurement of their utility in wholeorganisms 16.8 Studies of a drugs action in laboratory animals arean essential part of pre-clinical testing 16.9 Promising candidatedrugs are subjected to rigorous clinical tests in Phase I trials inhumans 16.10 Phase II and III trials provide credible indicationsof clinical efficacy 16.11 Tumors often develop resistance toinitially effective therapy 16.12 Gleevec paved the way for thedevelopment of many other highly targeted compounds 16.13 EGFreceptor antagonists may be useful for treating a wide variety oftumor types 16.14 Proteasome inhibitors yield unexpectedtherapeutic benefit 16.15 A sheep teratogen may be useful as ahighly potent anti-cancer drug 16.16 mTOR, a master regulator ofcell physiology, represents an attractive target for anti-cancertherapy 16.17 B-Raf discoveries have led to inroads into themelanoma problem 16.18 Synopsis and prospects: challenges andopportunities on the road ahead Key concepts Thought questionsAdditional reading761 765 769 773 774 778 781 785 786 791 793 795795797 800 806 813 815 818 822 825 826 829 831 833 834 844 850 855861 864 866 874 875 875 22. Chapter 1The Biology and Genetics ofCells and Organisms Protoplasm, simple or nucleated, is the formalbasis of all life... Thus it becomes clear that all living powersare cognate, and that all living forms are fundamentally of onecharacter. The researches of the chemist have revealed a no lessstriking uniformity of material composition in living matter.Thomas Henry Huxley, evolutionary biologist, 1868 Anything found tobe true of E. coli must also be true of elephants. Jacques Monod,pioneer molecular biologist, 1954The biological revolution of thetwentieth century totally reshaped all fields of biomedical study,cancer research being only one of them. The fruits of thisrevolution were revelations of both the outlines and the minutedetails of genetics and heredity, of how cells grow and divide, howthey assemble to form tissues, and how the tissues develop underthe control of specific genes. Everything that follows in this textdraws directly or indirectly on this new knowledge. Thisrevolution, which began in mid-century and was triggered by Watsonand Cricks discovery of the DNA double helix, continues to thisday. Indeed, we are still too close to this breakthrough toproperly understand its true importance and its long-termramifications. The discipline of molecular biology, which grew fromthis discovery, delivered solutions to the most profound problem oftwentieth-century biologyhow does the genetic constitution of acell or organism determine its appearance and function? Withoutthis molecular foundation, modern cancer research, like many otherbiological disciplines, would have remained a descriptive sciencethat cataloged diverse biological phenomena without being able toexplain the mechanics of how they occur.Movies in this chapter 1.1Replication I 1.2 Replication II 1.3 Translation I 1.4Transcription1 23. 2Chapter 1: The Biology and Genetics of Cellsand Organisms Figure 1.1 Darwin and Mendel (A) Charles Darwins 1859publication of On the Origin of Species by Means of NaturalSelection exerted a profound effect on thinking about the origin oflife, the evolution of organismic complexity, and the relatednessof species. (B) Darwins theory of evolution lacked a geneticrationale until the work of Gregor Mendel. The synthesis ofDarwinian evolution and Mendelian genetics is the foundation formuch of modern biological thinking. (A, from the Grace K. BabsonCollection, the Henry E. Huntington Library, San Marino,California. Reproduced by permission of The Huntington Library, SanMarino, California. B, courtesy of the Mendelianum Museum Moraviae,Brno, Czech Republic.)(A)(B)Today, our understanding of how cancersarise is being continually enriched by discoveries in diversefields of biological research, most of which draw on the sciencesof molecular biology and genetics. Perhaps unexpectedly, many ofour insights into the origins of malignant disease are not TBoC2b1.01a,b/1.01 coming from the laboratory benches of cancerresearchers. Instead, the study of diverse organisms, ranging fromyeast to worms to flies, provides us with much of the intellectualcapital that fuels the forward thrust of the rapidly moving fieldof cancer research. Those who fired up this biological revolutionstood on the shoulders of nineteenthcentury giants, specifically,Darwin and Mendel (Figure 1.1). Without the concepts established bythese two, which influence all aspects of modern biologicalthinking, molecular biology and contemporary cancer research wouldbe inconceivable. So, throughout this chapter, we frequently makereference to evolutionary processes as proposed by Charles Darwinand genetic systems as conceived by Gregor Mendel.1.1 Mendelestablishes the basic rules of geneticsMany of the basic rules ofgenetics that govern how genes are passed from one complex organismto the next were discovered in the 1860s by Gregor Mendel and havecome to us basically unchanged. Mendels work, which tracked thebreeding of pea plants, was soon forgotten, only to be rediscoveredindependently by three researchers in 1900. During the decade thatfollowed, it became clear that these ruleswe now call themMendelian geneticsapply to virtually all sexual organisms,including metazoa (multicellular animals), as well as metaphyta(multicellular plants). Mendels most fundamental insight came fromhis realization that genetic information is passed in particulateform from an organism to its offspring. This implied that theentire repertoire of an organisms genetic informationits genome, intodays terminologyis organized as a collection of discrete,separable information packets, now called genes. Only in recentyears have we begun to know with any precision how many distinctgenes are present in the genomes of mammals; many current analysesof the human genomethe best studied of theseplace the number in therange of 21,000, somewhat more than the 14,500 genes identified inthe genome of the fruit fly, Drosophila melanogaster. Mendels workalso implied that the constitution of an organism, including itsphysical and chemical makeup, could be divided into a series ofdiscrete, separable entities. Mendel went further by showing thatdistinct anatomical parts are controlled by distinct genes. Hefound that the heritable material controlling the smoothness ofpeas behaved independently of the material governing plant heightor flower color. In 24. Mendel establishes the basic rules ofgenetics Seed shapeSeed colorFlower colorFlower positionPodshapePod colorPlantheightroundyellowviolet-redaxialinatedgreentallwrinkledgreenwhiteterminalpinchedyellowshortOneform of trait (dominant)A second form of trait (recessive)Figure1.2 A particulate theory of inheritance One of Gregor Mendelsprincipal insights was that the genetic content of an organismconsists of discrete parcels of information, each responsible for adistinct observable trait. Shown are the seven pea-plant traitsthat Mendel studied through breeding experiments. Each trait hadtwo observable (phenotypic) manifestations, which we now know to bespecified by the alternative versions of genes that we callalleles. When the two alternative alleles coexisted within a singleplant, the dominant trait (above) was always observed while therecessive trait (below) was never observed. (Courtesy of J.Postlethwait and J. Hopson.)effect, each observable trait of anindividual might be traceable to a separate gene that served as itsblueprint. Thus, Mendels research implied that the geneticconstitution of an organism (its genotype) could be divided intohundreds, perhaps thousands of discrete information packets; inparallel, its observable, outward appearance (its TBoC2 b1.02/1.02phenotype) could be subdivided into a large number of discretephysical or chemical traits (Figure 1.2). Mendels thinking launcheda century-long research project among geneticists, who applied hisprinciples to studying thousands of traits in a variety ofexperimental animals, including flies (Drosophila melanogaster),worms (Caenorhabditis elegans), and mice (Mus musculus). In themid-twentieth century, geneticists also began to apply Mendelianprinciples to study the genetic behavior of single-celledorganisms, such as the bacterium Escherichia coli and bakers yeast,Saccharomyces cerevisiae. The principle of genotype governingphenotype was directly transferable to these simpler organisms andtheir genetic systems. While Mendelian genetics represents thefoundation of contemporary genetics, it has been adapted andextended in myriad ways since its embodiments of 1865 and 1900. Forexample, the fact that single-celled organisms often reproduceasexually, that is, without mating, created the need foradaptations of Mendels original rules. Moreover, the notion thateach attribute of an organism could be traced to instructionscarried in a single gene was realized to be simplistic. The greatmajority of observable traits of an organism are traceable to thecooperative interactions of a number of genes. Conversely, almostall the genes carried in the genome of a complex organism playroles in the development and maintenance of multiple organs,tissues, and physiologic processes.3 25. 4Chapter 1: The Biologyand Genetics of Cells and Organisms Mendelian genetics revealed forthe first time that genetic information is carried redundantly inthe genomes of complex plants and animals. Mendel deduced thatthere were two copies of a gene for flower color and two for peashape. Today we know that this twofold redundancy applies to theentire genome with the exception of the genes carried in the sexchromosomes. Hence, the genomes of higher organisms are termeddiploid. Mendels observations also indicated that the two copies ofa gene could convey different, possibly conflicting information.Thus, one gene copy might specify roughsurfaced and the othersmooth-surfaced peas. In the twentieth century, these differentversions of a gene came to be called alleles. An organism may carrytwo identical alleles of a gene, in which case, with respect tothis gene, it is said to be homozygous. Conversely, the presence oftwo different alleles of a gene in an organisms genome renders thisorganism heterozygous with respect to this gene. Because the twoalleles of a gene may carry conflicting instructions, our views ofhow genotype determines phenotype become more complicated. Mendelfound that in many instances, the voice of one allele may dominateover that of the other in deciding the ultimate appearance of atrait. For example, a pea genome may be heterozygous for the genethat determines the shape of peas, carrying one round and onewrinkled allele. However, the pea plant carrying this pair ofalleles will invariably produce round peas. This indicates that theround allele is dominant, and that it will invariably overrule itsrecessive counterpart allele (wrinkled) in determining phenotype(see Figure 1.2). (Strictly speaking, using proper geneticparlance, we would say that the phenotype encoded by one allele ofa gene is dominant with respect to the phenotype encoded by anotherallele, the latter phenotype being recessive.) In fact, classifyingalleles as being either dominant or recessive oversimplifiesbiological realities. The alleles of some genes may be co-dominant,in that an expressed phenotype may represent a blend of the actionsof the two alleles. Equally common are examples of incompletepenetrance, in which case a dominant allele may be present but itsphenotype is not manifested because of the actions of other geneswithin the organisms genome. Therefore, the dominance of an alleleis gauged by its interactions with other allelic versions of itsgene, rather than its ability to dictate phenotype. With suchdistinctions in mind, we note that the development of tumors alsoprovides us with examples of dominance and recessiveness. Forinstance, one class of alleles that predispose cells to developcancer encode defective versions of enzymes involved in DNA repairand thus in the maintenance of genomic integrity (discussed againin Chapter 12). These defective alleles are relatively rare in thegeneral population and function recessively. Consequently, theirpresence in the genomes of many heterozygotes (of awild-type/mutant genotype) is not apparent. However, twoheterozygotes carrying recessive defective alleles of the same DNArepair gene may mate. One-fourth of the offspring of such matingpairs, on average, will inherit two defective alleles, exhibit aspecific DNA repair defect in their cells, and develop certaintypes of cancer at greatly increased rates (Figure 1.3).1.2Mendelian genetics helps to explain Darwinian evolutionIn the earlytwentieth century, it was not apparent how the distinct allelicversions of a gene arise. At first, this variability in informationcontent seemed to have been present in the collective gene pool ofa species from its earliest evolutionary beginnings. Thisperception changed only later, beginning in the 1920s and 1930s,when it became apparent that genetic information is corruptible;the information content in genetic texts, like that in all texts,can be altered. Mutations were found to be responsible for changingthe information content of a gene, thereby converting one alleleinto another or creating a new allele from one previouslywidespread within a species. An allele that is present in the greatmajority of individuals within a species is usually termed wildtype, the term implying that such an allele, being naturallypresent in large numbers of apparently healthy organisms, iscompatible with normal structure and function. 26. Mendeliangenetics helps to explain Darwinian evolution allele:function ofallele product:wild-typeDNA repaired damaged DNAmutantDNAunrepairedDNA repair phenotypenormalnormalnormaldefectiveMutationsalter genomes continually throughout the evolutionary life span ofa species, which usually extends over millions of years. Theystrike the genome and its constituent genes randomly. Mutationsprovide a species with a method for continually TBOC2 n1.100/1.03tinkering with its genome, for trying out new versions of genesthat offer the prospect of novel, possibly improved phenotypes. Theresult of the continuing mutations on the genome is a progressiveincrease during the evolutionary history of a species in thegenetic diversity of its members. Thus, the collection of allelespresent in the genomes of all members of a speciesthe gene pool ofthis speciesbecomes progressively more heterogeneous as the speciesgrows older. This means that older species carry more distinctalleles in their genomes than younger ones. Humans, belonging to arelatively young species (1013 population size would suggest, sincethis number represents the average, steady-state population ofcells in the body at any point in time during adulthood. Theaggregate number of cells that are formed during an average humanlifetime is about 1016, a number that testifies to the enormousamount of cell turnoverinvolving cell death and replacement (almost107 events per second)that occurs continuously in many tissues inthe body. As discussed in Chapters 9 and 12, each time a new cellis formed by the complex process of cell growth and division, thereare many ways for things to go awry. Hence, the chance for disasterto strike, including the inadvertent formation of cancer cells, isgreat. Since a normal biological process (incessant cell division)is likely to create a substantial risk of cancer, it would seemlogical that human populations throughout the world wouldexperience similar frequencies of cancer. However, when cancerincidence rates (that is, the rates with which the disease isdiagnosed) are examined in various countries, we learn that therisks of many types of cancer vary dramatically (Table 2.5), whileother cancers (not indicated in Table 2.5) do indeed showcomparable incidence rates across the globe. So, our speculationthat all cancers should strike different human populations atcomparable rates is simply wrong. Some do and some dont. Thisrealization forces us to reconsider our thinking about how cancersare formed.Table 2.5 Geographic variation in cancer incidence anddeath rates Countries showing highest and lowest incidence ofspecific types of cancera Cancer siteCountry of highest riskCountryof lowest riskRelative risk H/LbSkin (melanoma)Australia(Queensland)Japan155LipCanada (Newfoundland)Japan151NasopharynxHongKongUnited Kingdom100ProstateU.S. (AfricanAmerican)China70LiverChina (Shanghai)Canada (NovaScotia)49PenisBrazilIsrael (Ashkenazic)42Cervix(uterus)BrazilIsrael (non-Jews)28StomachJapanKuwait22LungU.S.(Louisiana, African American)India (Madras)19PancreasU.S. (LosAngeles, Korean American)India11OvaryNew Zealand(Polynesian)Kuwait8Geographic areas showing highest and lowestdeath rates from specific types of cancerc Relative risk H/LbCancersiteArea of highest riskArea of lowest riskLung, maleEasternEuropeWest Africa33EsophagusSouthern AfricaWest Africa16Colon,maleAustralia, New ZealandMiddle Africa15Breast, femaleNorthernEuropeChinaaSee6C. Muir, J. Waterhouse, T. Mack et al., eds.,Cancer Incidence in Five Continents, vol. 5. Lyon: InternationalAgency for Research on Cancer, 1987. Excerpted by V.T. DeVita, S.Hellman and S.A. Rosenberg, Cancer: Principles and Practice ofOncology. Philadelphia: Lippincott, 1993. bRelative risk:age-adjusted incidence or death rate in highest country or area (H)divided by age-adjusted incidence or death rate in lowest countryor area (L). These numbers refer to age-adjusted rates, forexample, the relative risk of a 60-year-old dying from a specifictype of tumor in one country compared with a 60-year-old in anothercountry. cSee P. Pisani, D.M. Parkin, F. Bray and J. Ferlay, Int.J. Cancer 83:1829, 1999. This survey divided the human populationinto 23 geographic areas and surveyed the relative mortality ratesof various cancer types in each area. 78. Cancer incidence variesgreatly Some of the more than 100 types of human cancers do seem tohave a high proportion of tumors that are caused by random,unavoidable accidents of nature and thus occur with comparablefrequencies in various human populations. This seems to be true forcertain pediatric tumors. In addition to this relatively constantbackground rate of some specific cancers, yet other factors appearto intervene in certain populations to increase dramatically thetotal number of cancer cases. The two obvious contributory factorshere are heredity and environment. Which of these twoalternativesheredity or environmentis the dominant determinant ofthe country-to-country variability of cancer incidence? While manytypes of disease-causing alleles are distributed unequally in thegene pools of different human populations, these alleles do notseem to explain the dramatically different incidence rates ofvarious cancers throughout the world. This point is demonstratedmost dramatically by measuring cancer rates in migrant populations.For example, Japanese experience rates of stomach cancer that are 6to 8 times higher than those of Americans (Figure 2.23). However,when Japanese settle in the United States, within a generationtheir offspring exhibit a stomach cancer rate that is comparable tothat of the surrounding population. For the great majority ofcancers, disease risk therefore seems to be environmental, wherethis term is understood to include both physical environment andlifestyle. As indicated in Table 2.5, the incidence of some typesof cancer may vary enormously from one population to the next.Thus, breast cancer in China is about one-sixth as common as in theUnited States or Northern Europe. Having excluded geneticcontributions to this difference, we might then conclude that asmany as 85% of the breast cancers in the United States might intheory be avoidable, if only American women were to experience anenvironment and lifestyle comparable to those of their Chinesecounterparts. Even within the American population, there are vastdifferences in cancer mortality: the Seventh-Day Adventists, whosereligion discourages smoking, heavy drinking, and the consumptionof pork, die from cancer at a rate that is only aboutthree-quarters that of the general population. For those who wishto understand the etiologic (causative) mechanisms of cancer, thesefindings lead to an inescapable conclusion: the great majority ofthe commonly occurring cancers are caused by factors or agents thatare external to the body, enter into the body, and somehow attackand corrupt its tissues. In a minority of cancers, substantialvariations in cancer risk may be attributable to differences inreproductive behavior and the resulting dramatic effects on thehormonal environment within the human female body.cumulative rateby age 75 (%)151050prostatecolon (M) stomach (M) cancer typeOsaka19701971 Osaka 19881992breast (F)Hawaiian Japanese 19881992Hawaiian Caucasian 19681972 Hawaiian Caucasian 19881992Figure 2.23Country-to-country comparisons of cancer incidence Public healthrecords reveal dramatic differences in the incidence of certaincancers in different countries. Here, the relative incidences of agroup of cancers in Japan and in the American island of Hawaii arepresented. Invariably, after Japanese have immigrated to Hawaii,within a generation their cancer rates approach those of thepopulation that settled there before them. This indicates that thediffering cancer rates are not due to genetic differences betweenthe Japanese and the American populations. (From J. Peto, Nature411:390395, 2001.)57 79. 58Chapter 2: The Nature of Cancer Let usimagine, for the sake of argument, that avoidance of certainobvious cancercausing factors in diet and lifestyle resulted in a50% reduction in the risk of dying from cancer in the West, leavingthe disease of cancer as the cause of about 10% of overallmortality in this population. Under these conditions, given theapproximately 1016 mitoses occurring in each human body during anormal life span, we calculate that only 1 in 1017 celldivisionsthe total number of cell divisions occurring in the bodiesof 10 individuals during their lifetimeswould lead directly orindirectly to a clinically detectable cancer. Now, we becomepersuaded that in spite of the enormous intrinsic risk ofdeveloping cancer, the body must be able to mount highly effectivedefenses that usually succeed in holding off the disease for the 70or 80 years that most of us spend on this planet. These defensesare the subject of many discussions throughout this book.2.8 Therisks of cancers often seem to be increased by assignableinfluences including lifestyleEvidence that certain kinds ofcancers are associated with specific exposures or lifestyles isactually quite old, predating modern epidemiology by more than acentury. The first known report comes from the observations of theEnglish physician John Hill, who in 1761 noted the connectionbetween the development of nasal cancer and the excessive use oftobacco snuff. Fourteen years later, Percivall Pott, a surgeon inLondon, reported that he had encountered a substantial number ofskin cancers of the scrotum in adolescent men who, in their youth,had worked as chimney sweeps. Within three years, the Danishsweepers guild urged its members to take daily baths to remove theapparently cancer-causing material from their skin. This practicewas likely the cause of the markedly lower rate of scrotal cancerin continental Europe when compared with Britain even a centurylater. Beginning in the mid-sixteenth century, silver was extractedin large quantities from the mines in St. Joachimsthal in Bohemia,today Jchymov in the Czech Republic. By the first half of thenineteenth century, lung cancer was documented at high rates in theminers, a disease that was otherwise almost unheard of at the time.Once again, an occupational exposure had been correlated with aspecific type of cancer. In 1839, an Italian physician reportedthat breast cancer was a scourge in the nunneries, being present atrates that were six times higher than among women in the generalpopulation who had given birth multiple times. By the end of thenineteenth century, it was clear that occupational exposure andlifestyle were closely connected to and apparently causes of anumber of types of cancer. The range of agents that might triggercancer was expanded with the discovery in the first decade of thetwentieth century that physicians and others who experimented withthe then-recently invented X-ray tubes experienced increased ratesof cancer, often developing tumors at the site of irradiation.These observations led, many years later, to an understanding ofthe lung cancer in the St. Joachimsthaler miners: their greatlyincreased lung cancer incidence could be attributed to the highlevels of radioactivity in the ores coming from these mines.Perhaps the most compelling association between environmentalexposure and cancer incidence was forged in 1949 and 1950 when twogroups of epidemiologists reported that individuals who were heavycigarette smokers ran a lifetime risk of lung cancer that was morethan twentyfold higher than that of nonsmokers. The initial resultsof one of these landmark studies are given in Table 2.6. Thesevarious epidemiologic correlations proved to be critical forsubsequent cancer research, since they suggested that cancers oftenhad specific, assignable causes, and that a chain of causalitymight one day be traced between these ultimate causes and thecancerous changes observed in certain human tissues. Indeed, in thehalf century that followed the 19491950 reports, epidemiologistsidentified a variety of environmental and lifestyle factors thatwere strongly correlated with t 2ff7e9595c