Cytokines in the genesis and treatment of cancer

2007·5.4 MB·English

by  Caligiuri, Michael A

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
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byDavid A. Gerwitz, Shawn Edan Holtz, and Steven Grant, 2007
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2007
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Transforming Growth Factor-βββββ in Cancer Therapy, Volume II: Cancer Treatment and Therapy,
edited by Sonia Jakowlew, 2007
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bySonia Jakowlew, 2007
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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
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Immunotherapy of Cancer, edited by Mary L. Disis, 2006
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Kelloff, Ernest T. Hawk, and Caroline C. Sigman, 2005
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Kelloff, Ernest T. Hawk, and Caroline C. Sigman, 2004
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and Howard L. McLeod, 2004
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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.
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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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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