Cytokines in the Genesis and Treatment of Cancer PDF
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C G YTOKINES IN THE ENESIS T C AND REATMENT OF ANCER C D D D ANCER RUG ISCOVERY AND EVELOPMENT B A. T , S E EVERLY EICHER ERIES DITOR Antiangiogenic Agents in Cancer Therapy, Second Edition, edited by Beverly A. Teicher and Lee M. Ellis, 2007 Apoptosis and Senescence in Cancer Chemotherapy and Radiotherapy, Second Edition, edited byDavid A. Gerwitz, Shawn Edan Holtz, and Steven Grant, 2007 Molecular Targeting in Oncology, edited by Howard L. Kaufman, Scott Wadler, and Karen Antman, 2007 In Vivo Imaging of Cancer Therapy, edited by Anthony F. Shields and Patricia Price, 2007 Transforming Growth Factor-βββββ in Cancer Therapy, Volume II: Cancer Treatment and Therapy, edited by Sonia Jakowlew, 2007 Transforming Growth Factor-βββββ in Cancer Therapy, Volume 1: Basic and Clinical Biology, edited bySonia Jakowlew, 2007 Microtubule Targets in Cancer Therapy, edited byAntonio T. Fojo, 2007 Cytokines in the Genesis and Treatment of Cancer, edited by Michael A. Caligiuri and Michael T. Lotze, 2007 Regional Cancer Therapy, edited by Peter M. Schlag and Ulrike Stein, 2007 Gene Therapy for Cancer, edited by Kelly K. Hunt, Stephan A. Vorburger, and Stephen G. Swisher, 2007 Deoxynucleoside Analogs in Cancer Therapy, edited by Godefridus J. Peters, 2006 Cancer Drug Resistance, edited by Beverly A. Teicher, 2006 Histone Deacetylases: Transcriptional Regulation and Other Cellular Functions, edited by Eric Verdin, 2006 Immunotherapy of Cancer, edited by Mary L. Disis, 2006 Biomarkers in Breast Cancer: Molecular Diagnostics for Predicting and Monitoring Therapeutic Effect, edited by Giampietro Gasparini and Daniel F. Hayes, 2006 Protein Tyrosine Kinases: From Inhibitors to Useful Drugs, edited by Doriana Fabbro and Frank McCormick, 2005 Bone Metastasis: Experimental and Clinical Therapeutics, edited by Gurmit Singh and Shafaat A. Rabbani, 2005 The Oncogenomics Handbook,edited by William J. LaRochelle and Richard A. Shimkets, 2005 Camptothecins in Cancer Therapy,edited by Thomas G. Burke and Val R. Adams, 2005 Combination Cancer Therapy: Modulators and Potentiators, edited by Gary K. Schwartz, 2005 Cancer Chemoprevention,Volume 2:Strategies for Cancer Chemoprevention, edited by Gary J. Kelloff, Ernest T. Hawk, and Caroline C. Sigman, 2005 Death Receptors in Cancer Therapy, edited by Wafik S. El-Deiry, 2005 Cancer Chemoprevention,Volume 1:Promising Cancer Chemopreventive Agents, edited by Gary J. Kelloff, Ernest T. Hawk, and Caroline C. Sigman, 2004 Proteasome Inhibitors in Cancer Therapy, edited by Julian Adams, 2004 Nucleic Acid Therapeutics in Cancer, edited by Alan M. Gewirtz, 2004 DNA Repair in Cancer Therapy, edited by Lawrence C. Panasci and Moulay A. Alaoui-Jamali, 2004 Hematopoietic Growth Factors in Oncology: Basic Science and Clinical Therapeutics, edited by George Morstyn, MaryAnn Foote, and Graham J. Lieschke, 2004 Handbook of Anticancer Pharmacokinetics and Pharmacodynamics, edited by William D. Figg and Howard L. McLeod, 2004 Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval, Second Edition, edited by Beverly A. Teicher and Paul A. Andrews, 2004 Handbook of Cancer Vaccines, edited by Michael A. Morse, Timothy M. Clay, and Kim H. Lyerly,2004 C G YTOKINES IN THE ENESIS T C AND REATMENT OF ANCER Edited by M A. C , ICHAEL ALIGIURI MD The Ohio State University Comprehensive Cancer Center Columbus, OH M T. L , ICHAEL OTZE MD University of Pittsburgh Cancer Center Pittsburgh, PA © 2007 Humana Press Inc. 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 www.humanapress.com All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. All articles, comments, opinions, conclusions, or recommendations are those of the author(s), and do not necessarily reflect the views of the publisher. Due diligence has been taken by the publishers, editors, and authors of this book to assure the accuracy of the information published and to describe generally accepted practices. The contributors herein have carefully checked to ensure that the drug selections and dosages set forth in this text are accurate and in accord with the standards accepted at the time of publication. Notwithstanding, as new research, changes in government regulations, and knowledge from clinical experience relating to drug therapy and drug reactions constantly occurs, the reader is advised to check the product information provided by the manufacturer of each drug for any change in dosages or for additional warnings and contraindications. This is of utmost importance when the recommended drug herein is a new or infrequently used drug. It is the responsibility of the treating physician to determine dosages and treatment strategies for individual patients. Further it is the responsibility of the health care provider to ascertain the Food and Drug Administration status of each drug or device used in their clinical practice. The publisher, editors, and authors are not responsible for errors or omissions or for any consequences from the application of the information presented in this book and make no warranty, express or implied, with respect to the contents in this publication. Cover design by Donna Niethe Cover illustrations: B16–F10 melanoma cell-derived tumors generated in IL-5 transgenic mice display increased eosinophil accumulation in the necrotic and capsule regions with evidence of extensive eosinophil degranulation. Immunohistochemistry with the rabbit polyclonal anti-mouse MBP antisera demonstrated a dramatic eosinophilia in tumors from hypereosinophilic IL-5 transgenic mice, which replicated the spatial distribution observed in tumors from wild type mice (i.e., eosinophils accumulated only in the necrotic and capsule regions of the tumors). Higher magnification views of tumor sections revealed evidence of extensive eosinophil degranulation within the necrotic areas (i.e., diffuse reddish-purple extracellular matrix staining). Photographs were taken by Anna Taranova, Nancy Lee, and Jamie Lee (Mayo Clinic Arizona). 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The fee code for users of the Transactional Reporting Service is: [978-0-89603-820-2 • 0-89603-820-3/07 $30.00]. Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1 eISBN: 1-59745-455-9 Library of Congress Cataloging-in-Publication Data Cytokines in the genesis and treatment of cancer / edited by Michael A. Caligiuri, Michael T. Lotze. p. ; cm. -- (Cancer drug discovery and development) Includes bibliographical references and index. ISBN 978-0-89603-820-2 (alk. paper) 1. Cytokines--Therapeutic use. 2. Cancer--Chemotherapy. 3. Carcinogenesis. I. Caligiuri, Michael A. II. Lotze, Michael T. III. Series. [DNLM: 1. Cytokines--therapeutic use. 2. Neoplasms--therapy. 3. Cytokines--immunology. 4. Neoplasms--genetics. QZ 266 C997 2007] RC271.C95C982 2007 616.99'406--dc22 2007005215 For our families and those who have loved us, helped us, and supported us along the way F OREWORD Cancer initiation and progression reflect the combined effects of tumor cell- autonomous genetic alterations and the complex interplay of tumor cells with nontransformed host elements. Whereas intense effort has been directed towards elucidating the mechanisms by which mutations in oncogenes and tumor suppressors give rise to the hallmarks of cancer, increasing attention is being devoted to clarifying the role of host reactions in tumor pathogenesis. Hal Dvorak’s concept of cancer as a “wound that does not heal” has stimulated detailed investigations of the molecular pathways by which tumor cells subvert host factors released in response to tissue injury. While chronic inflammatory reactions usually fail to effectuate tissue repair, they may result in the persistent production of cytokines that, perhaps unintentionally, promote tumor cell growth, attenuate apoptosis, and facilitate angiogenesis, invasion, and metastasis. The delineation of these pathways and the recognition that they contribute to multiple stages of disease progression support the crafting of therapeutic strategies aimed at antagonizing these responses. In contrast to the diverse ways in which tumor cells may exploit host reactions, other compelling data indicate that the immune system sometimes may impede tumor development. Indeed, mice rendered immune deficient by gene targeting techniques display increased tumor susceptibility, and studies in immunocompetent animals illustrate that host responses profoundly shape the immunogenicity of nascent tumors. Despite these provocative findings, however, the formation of clinically evident tumors implies a failure of protective host reactions. Some of the mechanisms underlying this immune escape have been unraveled; these include inefficient tumor antigen presentation and negative immune regulatory circuits that normally function to maintain tolerance to self- antigens. These insights have provided a strong framework for devising new approaches to enhance antitumor immunity. Early-stage clinical testing of dendritic cell-based vaccines, defined immune adjuvants, antibodies that block regulatory pathways, adoptive transfer of antigen-specific T cells, and cytokine therapies have shown considerable promise. InCytokines in the Genesis and Treatment of Cancer, Drs. Caligiuri and Lotze bring together an impressive array of internationally distinguished investigators who are devoted to the study of cytokines and cancer. Collectively, these reviews provide a comprehensive picture of the dual role of host responses in promoting and inhibiting tumor progression. The emerging intersection of cancer biology and cancer immunology is creating synergies that should accelerate the design of efficacious therapies; this volume represents an important contribution to that effort. Glenn Dranoff, MD Dana-Farber Cancer Institute and Harvard Medical School Boston, MA vii viii Foreword Selected Reading Dvorak, H F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315, 1650-9 (1986). Hanahan, D and Weinberg, RA. The hallmarks of cancer. Cell 100, 57-70. (2000). Coussens, L and Werb, Z. Inflammation and cancer. Nature 420, 860-867 (2002). Dranoff, G. Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer 4, 11-22 (2004). Dunn, GP, Old, LJ, and Schreiber, RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21, 137-48 (2004). P REFACE A flea and a fly in a flue, Were imprisoned, so what could they do? Said the fly “Let us flee!” “Let us fly!” said the flea, And they flew through a flaw in the flue. 1. INTRODUCTION For over two decades it has been clear that cancer is a disease of the genes, associated with stepwise acquisition of mutations or molecular flaws arising in oncogenes and tumor suppressor genes that lead to abnormal cell death and unscheduled, reparative, cellular growth. More recently, it has also become clear that cancer in adults arises most often in the setting of chronic inflammation and that critical cytokines, the hormones that regulate cell growth, cell death, and cell function, also contribute to the pathogenesis of these cancers and can be commandeered to either prevent or treat patients with cancer. This volume collects the most exciting components of this evolving story so as to further cross- fertilize the worlds of immunology and oncology, enabling conception of novel interventions for the prevention and treatment of patients with cancer. In addition, we provide an up-to-date summary and assessment of the use of cytokines in harnessing components of the body’s immune and hematopoietic systems for the direct and supportive treatment of patients with cancer. 2. CYTOKINE BIOLOGY The components of the immune system, including cytokines and the cells they act on, sit between inflammation and the genesis of cancer. Cytokines are largely released by immune cells in response to tissue inflammation caused by danger, damage, or injury secondary to either infection (providing so-called pathogen-associated molecular patterns or PAMPs, cueing inflammatory cells) or chemical/physical induced cellular damage- associated molecular patterns or DAMPs (similarly driving recruitment and activation of myeloid cells). If such insults cannot be resolved quickly, chronic cytokine deregulation can contribute to the initiation and progression of cancer through a variety of mechanisms detailed in the ensuing chapters. The dizzying array of malignancies most commonly associated with chronic inflammation as the result of infection or chemical injury include bladder cancer from infection with schistosomiasis or analine dye exposure, lung cancer from smoking or asbestos exposure, colon cancer subsequent to inflammatory bowel disease and excessive red meat consumption, gastric cancer from Helicobacter pylori infection, cervical cancer arising in the setting of human papilloma virus, skin cancer from ultraviolet irradiation or chronic ulceration, esophageal cancer from gastric acid reflux, esophageal and head and neck cancer from excessive alcohol and/or tobacco consumption, hepatocellular carcinoma from hepatitis B or hepatitis C viral infections, lymphoma from Epstein-Barr virus infection, and lymphoma or Kaposi’s sarcoma from human herpes virus 8 infection. In some instances, the chronic use of anti-inflammatory ix x Preface agents has been associated with a lower incidence of cancer, lending further support to the role of chronic inflammation in the etiology of cancer. 3. MOLECULAR MECHANISMSOF CYTOKINE ASSOCIATED CARCINOGENESIS The molecular mechanisms used by cytokines to initiate or promote carcinogenesis are fascinating yet varied and incompletely understood. Several insights derived from in vitro systems and mouse models are covered in the first two parts of this text. The cytokine macrophage-migration inhibitory factor, an active component of both local and systemic inflammation, is capable of functionally inactivating the tumor suppressor p53 as well as the Rb-E2F pathway (1,2), whereas dysregulation of IL-15 is associated with acute leukemia and a genome-wide, nonrandom methylation in the 5(cid:1)regulatory regions of select genes that results in their silencing (3). The interleukin-1 [IL-1] gene is polymorphic, some variants of which strongly associate with altered secretion and the subsequent development of gastric cancer (4), appearing to be important for both tumor invasion and angiogenesis (5). TNF inhibits skeletal muscle differentiation by suppressing MyoD mRNA at the post-transcriptional level and inducing NFκB(6). These changes are associated with comorbid conditions including cancer-associated muscle wasting or cachexia, described in detail in Chapter 16. The chapters contained within the first half of this book detail the diverse ways that individual host cytokines contribute to cancer initiation and cancer progression. Thus neutralization or disruption of their effect on host tissues should presumably prevent cancer, slow its progression, or favorably alter the threshold for apoptosis in the context of cytotoxic anticancer therapy. Most recent studies are consistent with the notion that life in the tumor microenvironment is indeed disordered, associated with hypoxia, mitotic catastrophe, autophagy, and frank necrosis and apoptosis—all means of death driven by genomic instability and chronic inflammation. In experimental animal models, elimination or neutralization of individual cytokines can adversely impact the genesis of cancer, often arising in the setting of chronic inflammation. For example, although TGF- βlikely promotes the late stages of colon carcinogenesis, its absence in Rag2deficient mice renders them more susceptible to the spontaneous development of colon cancer only when these mice are not maintained under pathogen-free conditions (ref.7and Chapter 5). It is more likely that a balanced symphony of cytokines is required to finely regulate tissue homeostasis, responding to tissue damage in some instances, and in others promoting neoplastic progression and reparative expansion of neoplastic clones. Elimination of any one cytokine may go unnoticed because of redundancy or may advance local environmental dysfunction in a way that exacerbates inflammation because of unexpected pleiotropy or unopposed action of other mutually antagonistic cytokines. A multitude of such scenarios is considered throughout this treatise and the results are carefully interpreted in the context of these experimental systems. The first three chapters focus on the interface of cytokines with three infectious agents, H. pylori,HTLV-1, and human herpes viruses associated with the genesis of cancer. In each instance, only a small fraction of individuals infected with these agents eventually develop cancer. Gastric infection with H. pylori induces a persistent proinflammatory cytokine response, resulting in malignant transformation depending on the host’s immune response genes along with the individual pathogen’s virulence factors. Although infection with HTLV-1 is endemic in many regions of the world, the molecular mechanisms used
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