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Published by World Scientific Publishing Co. Pte. Ltd. 5 Toh Tuck Link, Singapore 596224 USA office: 27 Warren Street, Suite 401-402, Hackensack, NJ 07601 UK office: 57 Shelton Street, Covent Garden, London WC2H 9HE British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. HUMAN ONCOGENIC VIRUSES Copyright 2010 by World Scientific Publishing Co. Pte. Ltd. All rights reserved. This book, or parts thereof, may not be reproduced in any form or by any means, electronic or mechanical, including photocopying, recording or any information storage and retrieval system now known or to be invented, without written permission from the Publisher. For photocopying of material in this volume, please pay a copying fee through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA. In this case permission to photocopy is not required from the publisher. ISBN-13 978-981-283-346-4 ISBN-10 981-283-346-3 Typeset by Stallion Press Email: enquiries@stallionpress.com Printed in Singapore.
Foreword Viruses cause more than a fourth of all human cancers. Virus-induced cancers, like all viral diseases, present special challenges and raise specific hopes. The challenges are in understanding the molecular mechanism of the disease, knowing the mode of virus transmission, and obtaining global epidemiological data. The hope is for the development of effective vaccines, antiviral therapies and, ultimately, for the control and eradication of the pathogenic virus. This book presents a comprehensive survey of human cancer viruses. They include five viral families, the papillomaviruses, herpesviruses, hepadnaviruses, flaviviruses and retroviruses. For most of these cancer viruses, there is a good understanding of transmission, and epidemiological data are extensive. Indeed, epidemiological data have traditionally been essential for establishing the oncogenicity of a virus in humans. The viruses considered here have widely differing impacts on public health. The hepatitis viruses cause acute and chronic infections with significant morbidity and affect millions of people. Infection with oncogenic papillomaviruses is similarly widespread. Papilloma and hepatitis viruses have therefore been the focus of vaccine efforts. These efforts have succeeded for hepatitis B virus and for papillomaviruses; they are still in progress for hepatitis C virus. Kaposi sarcoma herpes virus and human T cell leukemia virus affect much smaller groups of people that are well defined by risk factors and geography. Our understanding of the molecular mechanisms of viral carcinogenesis in humans shows notable gaps. For some viruses, like the oncogenic papilloma and herpesviruses and for human T cell leukemia v
vi Foreword virus, specific proteins have been identified that interact with the growth-regulatory machinery of the cell and that play key roles in the oncogenic transformation process. For other viruses, like hepatitis B and hepatitis C viruses, such relationships between viral gene products and cellular regulation are less definitive. The molecular as well as epidemiological insights into human cancer viruses can be summarized in a single conclusion: These viruses are essential, causative components of the oncogenic process, yet they do not act alone. They are necessary, but not sufficient. Other factors play important roles, and many remain to be defined. Human cancer virology is now a mature field of science, and most of the groundbreaking discoveries have been made. This state of cancer virology invites historical reflection. The initial events that linked viruses to cancer were the discoveries of Ellermann and Bang and of Rous. It took several decades before this basic link was extended to human medicine. The association of the Epstein Barr herpes virus with Burkitt lymphoma and with nasopharyngeal carcinoma was an early signal. Shortly thereafter, hepatitis B virus, human T cell leukemia virus and carcinogenic human papillomaviruses all appeared on the scene. Kaposi sarcoma herpes virus and hepatitis C virus joined the ranks of human tumor viruses later. True discoveries are always unexpected and surprising; each of the critical events that shaped human tumor virology has these attributes. Ingenuity, hard work, instinct, perseverance and serendipity all played a role. The list of groundbreaking discoveries, all under the intellectual ancestry of Ellermann and Bang and of Rous, is short: Epstein and Barr and the Epstein-Barr herpes virus; Beasley and the connection between hepatocellular carcinoma and hepatitis B virus; zur Hausen and the causation of cervical cancer by papillomaviruses; Yoshida and Gallo and human T cell leukemia virus; and Chang and Moore and Kaposi sarcoma herpes virus. The connection between hepatitis C virus and hepatocellular carcinoma emerged more gradually from clinical and epidemiological observations, and credit for this insight is more widely distributed. Most of these openings were achieved by young scientists. Chang and Moore discovered Kaposi sarcoma herpes virus when they were in their middle thirties. Zur Hausen, Beasley,
Foreword vii Epstein and Barr, Yoshida and Gallo were still in their forties when they achieved their breakthroughs. And not all of these discoveries came from established virology labs. Chang and Moore worked outside the virology mainstream and did not even have grant support when they made their spectacular discovery. Beasley s perspective appropriately focused on public health and epidemiology; a molecular approach toward hepatitis B virus and cancer would not have been successful at the time. The igniting spark for the discovery of human T cell leukemia virus came from epidemiological studies that had revealed a unique, geographically confined T cell leukemia in southern Japan. Government support for medical research has sharply tightened over the past few years. In the US, the structure of funding and the allocation of resources have changed significantly. There has been a shift away from investigator-initiated projects that have been the source of most innovations and breakthroughs. The emphasis is now on larger conglomerate structures. With this collectivization of research funds has come extreme risk avoidance and support of the predictable and the mundane. Few of the research projects that have led to paradigm shifts in cancer virology would be fundable today. The consequences of these developments have been especially severe for young investigators. There is deep concern in the scientific community that much young talent is turned away and lost to science. However, there are now also some encouraging signs that the mechanism for public support of research has become flexible again. Scientists have a great stake in the restoration of individual initiative, prudent risk taking and the spirit of discovery in science funding, and there is hope that this will be possible. Reading this book and reflecting on the history and the challenges of the cancer virus field will inspire the insight, wisdom and excitement that are needed to advance science. Peter V. Vogt, PhD The Scripps Research Institute La Jolla, California March 24, 2009
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Preface A relationship between viruses and neoplasia has been suspected ever since the turn of the 20th century, when Ellerman and Bang, followed by Rous, showed that cell-free extracts of a chicken leukemia and sarcoma, respectively, induced the same disease upon inoculation into healthy chickens (Chapter 1). These observations eventually led to the unequivocal demonstration that several viruses of different families can cause malignancies in animals. The hunt was thus on, to search for similar viruses that may cause human cancers. Initially, the biomedical community was disappointed by the lack of positive results, until Epstein, Achong, and Barr demonstrated that Burkitt s lymphoma cells cultured in vitro contained a herpesvirus, subsequently named the Epstein-Barr virus. However, the ubiquity of this virus meant that the possibility of its merely being a passenger in the lymphoma cells could not be ruled out. The situation changed dramatically with the seminal epidemiological work of Beasley and colleagues, showing that hepatitis B virus infection in men was associated with a dramatic increase in risk of primary liver cancer in Taiwan; this association has since been proven to be causal (Chapter 2). More recently, hepatitis C virus, an entirely unrelated virus, has also been shown to cause liver cancer (Chapter 3). Similarly, the Nobel Prize-winning work of zur Hausen and colleagues revealed that certain types of human papillomaviruses cause cancers of the uterine cervix and other epithelial tissues, such as the oropharynx (Chapter 4). Indeed, the National Institute of Environmental Health and Safety (http://ntp.niehs.nih.gov/ntp/roc/toc11.html) lists these viruses as known human carcinogens. Human oncogenic viruses ix
x Preface are not limited to these three, however. Two γ-herpesviruses, the above-mentioned Epstein-Barr virus and the Kaposi s sarcoma herpes virus (also known as human herpesviruses 4 and 8, respectively), cause lymphoid as well as non-lymphoid neoplasms (epithelial cancers for the former, endothelial tumors for the latter) (Chapters 5 and 6, respectively). Finally, the human retrovirus human T-cell leukemia virus I, a distant relative of the Rous sarcoma virus, gives rise to leukemia (Chapter 7). Undoubtedly, additional viruses that cause human malignancies will be discovered or confirmed in the future, with members of the polyomaviruses being the most likely candidates (Chapter 1). It has been estimated that each year approximately 1.3 million people develop malignancies caused by these viruses (D. M. Parkin, 2006. Int J Cancer 118: 3030 3044). The majority of them (up to 1 million people) will die from their cancers. This number does not include death from other diseases caused by these viruses (e.g. cirrhosis in chronic hepatitis B or C), nor does it account for the lost productivity from chronic illness and the cost of medical treatment. These viruses clearly represent an extraordinary burden on global human health as well as an enormous drag on economic resources. This book aims to give a concise yet comprehensive and up-to-date view of these viruses. The reader will see that in addition to the expected differences among these disparate viruses, there are commonalities as well. One is that, unlike the case for Rous sarcoma virus and similar oncoretroviruses, a long latency period of chronic infection prior to neoplastic transformation is the rule. Thus, secondary genetic and/or epigenetic changes in the host genome, in addition to mutations in the viral genome, are likely critical for oncogenesis. Another similarity is that only a minority of people infected by each of the viruses develop neoplasia, implying the importance of co-factors, both environmental and genetic. Perhaps the most striking similarity is that each virus appears to have multiple independent mechanisms that can contribute to oncogenesis, ranging from dysregulation of cell growth and loss of genomic integrity to induction of inflammation, cell injury, and regeneration. Thus, it is unlikely that a single magic bullet can block malignant transformation of an infected cell, and
Preface xi the best therapy for virus-associated cancers is to prevent infection in the first place. This goal has been achieved for hepatitis B virus and the most common oncogenic human papillomaviruses, with the development of effective vaccines. Unfortunately, many of the populations most at risk of being infected by these viruses cannot obtain the vaccines, mostly for economic reasons. In any case, large numbers of people in the world are already infected. Therefore, the neoplasms caused by these viruses, as well as the other viruses presented in this book, will unfortunately afflict humankind for many more decades to come. Thus, the importance of understanding these viruses and their pathogenesis cannot be overstated. It is hoped that readers of this book will be inspired to continue the ground-breaking research described herein and develop new, more effective treatments for these viruses and the cancers that they cause. T.S. Benedict Yen and J.-H. James Ou
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Contents Foreword Preface Chapter 1 Oncogenic Viruses, Cellular Transformation 1 and Human Cancers Yanyan Zheng and Jing-hsiung James Ou Chapter 2 Hepatitis B Virus and Hepatocellular 41 Carcinogenesis T. S. Benedict Yen Chapter 3 Molecular Mechanism of Hepatitis C Virus 93 Carcinogenesis Keigo Machida, Jing-hsiung James Ou and Michael M. C. Lai v ix Chapter 4 Human Papillomaviruses and Associated 137 Malignancies Christine L. Nguyen, Margaret E. McLaughlin-Drubin and Karl Münger Chapter 5 Epstein-Barr Virus and Its Oncogenesis 209 Hsin-Pai Li, Mei Chao, Shu-Jen Chen and Yu-Sun Chang xiii
xiv Contents Chapter 6 Human Kaposi s Sarcoma-associated Herpesvirus: 269 Molecular Biology and Oncogenesis Patrick J. Dillon and Blossom Damania Chapter 7 Human T-Cell Leukemia Virus 1 and Cellular 317 Transformation Ya-Hui Chi and Kuan-Teh Jeang Index 335