Table Of ContentMacrophages
and
Cancer
Editors
Gloria H. Heppner, Ph.D.
Senior Vice President and Chairman
Department of Immunology
Michigan Cancer Foundation
Detroit, Michigan
Amy M. Fulton, Ph.D.
Associate Member
Department of Immunology
Michigan Cancer Foundation
Detroit, Michigan
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PREFACE
The role of macrophages incancer has received much attention inrecent years without a
consensus being reached regarding the precise mechanisms and influences operating on the
interactions between macrophages and tumor cells. Nevertheless, macrophage biologists
have made notable advances in understanding the complexity of macrophage phenotypes
and functions. This complexity has multiple origins. One is the phenotypic heterogeneity
of the group of cells collectively referred to as macrophages. As Morahan et al. discusses
in Chapter 1whether the underlying basis of this heterogeneity reflects the differentiation
lineage of a single cell type or whether macrophages are multiple, unrelated populations is
not yet known. Irregardless, it is necessary to appreciate that such heterogeneity exists and
that "macrophages" are mixed populations of cells with quite different functions and po-
tentials.
A second basis for the complexities of macrophage-tumor cell interactions isthe multiple
mechanisms involved in macrophage activation and effector function. Two groups of in-
vestigators, Adams and Hamilton and Stewart et al., both here review in Chapters 2 and 3
themolecular mechanisms ofmacrophage activity but, interestingly, from twovery different
and novel perspectives: one focuses on the events occurring in the macrophage, the other
on macrophage induced responses in the tumor cell.
An important class of regulatory mediators of macrophage function, and one which can
beaffected bytumorcells, aretheprostaglandins. Zwilling andJustement discuss inChapter
4thepositive and negative regulatory effects ofthesemolecules andtheircoupling to adenyl
cyclase activation inthe macrophage. Ofcourse, the relationship between macrophages and
tumor cells is subject to numerous regulatory influences. The genetic basis for control of
macrophage function is being unraveled by a combination of classical genetic experiments
and molecular approaches, as described by Stevenson and Skamene in Chapter 5.
Although itisapparentthatourgeneralunderstandingofmacrophagebiologyisincreasing,
our ability to realize the therapeutic potential of this class of inflammatory cells in the
treatment of cancer depends upon a parallel understanding of the biology of cancer cells.
The heterogeneity of macrophages is matched, if not exceeded, by that of tumor cell pop-
ulations. Indeed, as discussed by Fulton in Chapter 6, these two types of heterogeneity can
impact upon each other in influencing the types of macrophages which infiltrate different
tumors. Other players inthe host tumor cell scenario are lymphocytes, which independently
affect tumor cells, macrophages, and the interactions between them. Urban et al. describe
in Chapter 7 an example of this latter principle in which T cells mediate the appearance of
macrophage-résistant tumor cell variants. The theme of the interrelationship of tumor cell
heterogeneity and macrophage heterogeneity is also taken up by North et al. who describe
inChapter 8thebiologic consequences oftumorcellheterogeneity inregard to susceptibility
to macrophage effector functions.
Despite the formidable problems posed by multiple regulatory mechanisms and by ma-
crophageand tumor heterogeneity, there have been some remarkable advances in the ther-
apeuticuseofmacrophages. FoglerandFidlerdescribeinChapter9thepreclinical development
ofeffective macrophage-based therapies, and Kirsh et al. discuss inChapter 10some of the
strategies necessary to bring these new treatments to clinical reality.
The final chapter (Heppner and Dorcey) of this book is concerned with a role different
from the primarily defensive activities of macrophages in tumor development. There is
increasing evidence that macrophages might be a driving influence in the development and
heterogeneity of tumor cell populations. The mechanisms by which this occurs, althought
incompletely understood, mayberelated, paradoxically, tothose which mediate the defense
reactions. Macrophages are also the sources of angiogenic factors, growth factors and in-
vasion related proteases that may contribute positively to tumor growth and metastasis.
The relationship between tumor cells and macrophages is not a simple bidirectional in-
teraction, but rather a complex network of multifactorial processes. The topics inthis book
have been selected to highlight recent advances inour knowledge of these processes and to
illustrate how this knowledge may ultimately be used to help control neoplastic growth.
Gloria H. Heppner
Amy M. Fulton
THE EDITORS
Gloria H. Heppner, Ph.D., is the Senior Vice President of the Michigan Cancer Foun-
dationinDetroit. SheisalsoanAdjunct Professor ofPathology, Immunology, andBiological
Sciences at Wayne State University.
Dr. Heppner received her B.A., M.A., and Ph.D. degrees from the University of Cali-
fornia, Berkeley in 1962, 1964, and 1967, respectively. Her graduate training was in the
Cancer Research Genetics Laboratory under the direction of Dr. David Weiss. She was a
post-doctoral fellow from 1967 to 1969 at the University of Washington, Seattle in the
laboratories of Drs. Karl-Eric and Ingegerd Hellstrom.
Before joining the Michigan Cancer Foundation in 1979, Dr. Heppner was on the faculty
ofBrown University, Providence, RhodeIslandandwasanAssociate DirectoroftheBrown-
Roger Williams General Hospital Cancer Center. She is a member of several scientific
societies, including the American Association of Immunologists and the American Asso-
ciation forCancer Research. Shehasbeenamemberofseveral study sectionsoftheNational
Institutes of Health and a Chairman of the Bladder Cancer Working Group of the Organ
Sites Program of the National Cancer Institute.
Dr. Heppner's research interestshavecenteredontwoareas:theimmuneand inflammatory
responses to cancers and the development and consequences of cellular heterogeneity in
murine mammary tumors.
Amy M. Fulton, Ph.D. is Associate Member and Chief of the Laboratory of Immuno-
biology in the Department of Immunology at the Michigan Cancer Foundation in Detroit,
Michigan. She is an Adjunct Assistant Professor in the Department of Pathology at the
Wayne State University Medical School.
She received her B.A. at the University of Kansas in Lawrence in 1972 where she was
elected to Phi Beta Kappa. She received her Ph.D. in Medical Microbiology from the
University of Wisconsin, Madison in 1977. Dr. Fulton was a National Institutes of Health
post-doctoral fellow at the University of British Columbia, Vancouver, Canada for 2 years.
She is a member of the American Association for Cancer Research and the American
Association of Immunologists.
Since 1980, Dr. Fulton's research efforts have involved the study of the immunologic
response to breast cancer and the role that inflammatory mediators (prostaglandins and
reactive-oxygen intermediates) play in tumor growth and metastasis.
CONTRIBUTORS
Dolph O. Adams, M.D., Ph.D. Gloria Heppner, Ph.D.
Professor and Director Senior Vice President
Department of Pathology and Department of Immunology
Immunology Michigan Cancer Foundation
Duke University Medical Center Detroit, Michigan
Durham, North Carolina
John B. Hibbs, Jr., M.D.
Peter J. Bugelski, Ph. D. Professor
Smith Kline and French Laboratories Department of Medicine
Philadelphia, Pennsylvania University of Utah School of Medicine
Salt Lake City, Utah
Walla L. Dempsey, Ph.D.
Assistant Professor Tatsuro Irimura, Ph.D.
Department of Microbiology and Assistant Professor
Immunology Department of Tumor Biology
Medical College of Pennsylvania M. D. Anderson Hospital
Philadelphia, Pennsylvania and Tumor Institute
Houston, Texas
Leslie Dorcey, B.S.
Department of Immunology William J. Johnson, Ph. D.
Michigan Cancer Foundation Smith Kline and French Laboratories
Detroit, Michigan Philadelphia, Pennsylvania
Isaiah J. Fidler, D.V.M., Ph.D. Louis B. Justement, Ph.D.
Chairman and Professor Divisional Immunology
Department of Cell Biology National Jewish Center for
M. D. Anderson Hospital Immunology and Respiratory Medicine
and Tumor Institute Denver, Colorado
Houston, Texas
Richard Kirsh, Ph.D.
William E. Fogler, Ph.D. Department of Immunology
Senior Research Scientist Smith Kline and French Laboratories
Department of Immunobiology Philadelphia, Pennsylvania
Research and Development
Centocor Incorporated Meryle J. Melnicoff, M.S.
Malvern, Pennsylvania Senior Scientist
Department of Immunology and Anti-
Amy M. Fulton, Ph.D. Infectives
Associate Member Smith Kline and French Laboratories
Department of Immunology Swedeland, Pennsylvania
Michigan Cancer Foundation
Detroit, Michigan Page S. Morahan, Ph.D.
Professor and Chairman
Thomas A. Hamilton, Ph.D. Department of Microbiology and
Section on Atherosclerosis Immunology
Cleveland Clinic Foundation Medical College of Pennsylvania
Cleveland, Ohio Philadelphia, Pennsylvania
Garth Nicolson, Ph.D. Anita P. Stevenson, M.S.
Professor and Chairman Experimental Pathology Group
Department of Tumor Biology Life Sciences Division
University of Texas Los Alamos National Laboratory
M. D. Anderson Hospital and Tumor Los Alamos, New Mexico
Institute
Houston, Texas Mary M. Stevenson, Ph.D.
Assistant Professor
Susan M. North, Ph.D. Department of Medicine
Assistant Professor McGill University
Department of Tumor Biology Montreal, Quebec, Canada
M. D. Anderson Hospital and Tumor
Institute Carleton C. Stewart, Ph.D.
Houston, Texas Experimental Pathology Group
Life Sciences Division
George Poste, D.V.M., Ph.D. Los Alamos National Laboratory
Department of Research and Development Los Alamos, New Mexico
Smith Kline and French Laboratories
Philadelphia, Pennsylvania
James Loron Urban, Ph.D.
Postdoctoral Fellow
Jay L. Rothstein Department of Biology
Department of Pathology
Leukemia Society of America
Immunology Group
California Institute of Technology
University of Chicago
Pasadena, California
Chicago, Illinois
Hans Schreiber, M.D., Ph.D. Alvin Volkman, Ph.D.
Professor Professor
Department of Pathology Department of Pathology
University of Chigago East Carolina University School of Medicine
Chicago, Illinois Greenville, North Carolina
Emil Skamene, Ph.D. Bruce S. Zwilling, Ph.D.
Professor Professor
Faculty of Medicine Department of Microbiology
McGill University Ohio State University
Montreal, Quebec, Canada Columbus, Ohio
TABLE OF CONTENTS
Chapter 1
Macrophage Heterogeneity 1
Page S. Moraban, Al vin Volkman, Meryle Melnicoff, and Walla L. Dempsey
Chapter 2
Activation of Macrophages for Tumor Cell Kill: Effector Mechanisms and
Regulation 27
Dolph O. Adams and Thomas A. Hamilton
Chapter 3
Effector Mechanisms for Macrophage-Induced Cytostasis and Cytolysis of
Tumor Cells 39
Carleton C. Stewart, Anita P. Stevenson, and John Hibbs
Chapter 4
Prostaglandin Regulation of Macrophage Function 61
Bruce S. Zwilling and Louis B. Justement
Chapter 5
Genetic Control of Macrophage Antitumor Responses 79
Mary M. Stevenson and Emil Skamene
Chapter 6
Tumor Associated Macrophages 97
Amy M. Fulton
Chapter 7
Macrophage-Lymphocyte Interactions in Tumor Recognition and Response 113
James L. Urban, Jay L. Rothstein, and Hans Schreiber
Chapter 8
Heterogeneity in Tumor and Macrophage Populations in the Recognition, Cytostasis,
and Cytolysis of Neoplastic Cells 129
Susan M. North, Tatsuro Irimura, and Garth L. Nicolson
Chapter 9
Therapeutic Circumvention of the Biologic Heterogeneity in Malignant Neoplasms by
Tumoricidal Macrophages 147
William E. Fogler and Isaiah J. Fidler
Chapter 10
Strategies for Activation of Macrophages in Vivo for the Therapy of Metastatic
Disease 169
Richard Kirsh, William J. Johnson, Peter J. Bugelski, and George Poste
Chapter 11
Macrophages and Development of Cancer 197
Gloria Heppner and Leslie Dorcey
Index 209
1
Chapter 1
MACROPHAGE HETEROGENEITY
Page S. Moraban, Alvin Volkman, Meryle Melnicoff, and Walla L. Dempsey
TABLE OF CONTENTS
I. Introduction 2
II. Terms Used in Discussing MP Heterogeneity 3
III. Experimental Approaches Used to Document MP Heterogeneity 6
IV. Unanswered Questions Concerning the Origin of MP Heterogeneity 7
V. Experimental Evidence Concerning the Origin of MP Heterogeneity 7
A. Historical Comments 7
B. Phylogenetic Considerations 8
C. Role of Ontogeny in MP Heterogeneity 9
D. Role of the Blood Monocyte in MP Heterogeneity 10
E. Studies on the Role of the Monocyte in Inflammation 12
VI. Implications of MP Heterogeneity for Cancer 13
A. Theoretical Implications 13
B. Practical Considerations for Tumor Diagnosis, Immunity, Infection,
and Immunotherapy 13
1. Are the MPs within Tumors Primarily Derived from
Inflammatory Monocytes, or from Proliferation and
Differentiation/Activation of Resident MOs? 13
2. Do the Tumor Associated MO Populations Change
During Tumor Development? 14
3. Which Types of MPs will "Home" the Most Selectively to
Tumors? 14
4. Do Certain MPs Enhance Tumor Progression? 14
5. In MP Populations that Exhibit Apparently Antagonistic
Functions, do the Same MPs Exhibit these Functions
Simultaneously or is the Apparent Antagonism
due to Mixed MP Populations? 14
6. How do Tumors Change MP Trafficking and MP Functions for
Nonantitumor Functions? 15
VII. Conclusions and Future Approaches 15
Acknowledgments 16
References 16
