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 ■ PREFACE 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 inter- ested 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. Signal- ing pathways are composed of molecules that interact with other mole- cules, 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 cel- lular 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 identifi - cation of the malfunctions of specifi c 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 fi rst half discusses the cell and molecular biology of a specifi c 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 fi rst half of the chap- ter 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 tar- get DNA repair, microRNAs, and reprogramming energy metabolism. Deservedly, a section on the immune system has been added to the chapter on infection and infl ammation 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 supplemen- tary for some cancer courses. The fi nal 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 fi gures, artistically created by Joseph Pecorino. Major points and new cancer viii PREFACE therapeutics are illustrated in red, and the target symbol () is used to iden- tify molecular targets. Detailed descriptions of the fi gures 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 per- spectives of core concepts. Many times questions are posed; sometimes they are answered and other times they encourage the rereading of particu- lar sections of text. How do we know that? These features examine experimental evidence from the scientifi c litera- ture 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 can- cer risk, based on our current knowledge. Leaders in the fi eld of . Scientists around the world have made contributions to the concepts pre- sented in this text. Short biographies of several leading scientists, includ- ing their major contributions to a particular fi eld 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 scientifi c conferences. PREFACE ix Analysis of . Specifi c molecular techniques used to analyze particular biological and cellular events are described. It is important that science and medical pro- fessionals ask themselves “How do we know that?”. Each of the major concepts underlying our current state of knowledge is the result of numer- ous 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 particu- lar concepts presented in the chapter: Self tests presented within the text ask you to immediately reinforce material just presented and often refer to a fi gure. This causes a break from reading and engages you, the student, in “active” learning. Activities that are aimed at strengthening your under- standing of particular concepts and encouraging additional self-centered learning are presented towards the end of a chapter. Some require web- based research, while others are more refl ective. 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 con- tents of the chapter. They are not referenced in the main body of the text. Selected special topics mainly lists specifi c 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 search- ing for research posts and employment in the fi eld. Entries are separated by location (USA and UK). x PREFACE Glossary Over 160 entries are defi ned in a clear and concise manner in order to pro- vide students with a handy reference point for fi nding 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 fi eld of cancer biology. This fi eld 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. ■ ACKNOWLEDGMENTS First, I would like to express my deepest gratitude to Jonathan Crowe, Commissioning Editor, at Oxford University Press (OUP).