The Inflammatory Milieu of Tumors: Cytokines and Chemokines that Affect Tumor Growth and Metastasis


by

Adit B.-Baruch

DOI: 10.2174/97816080525611120101
eISBN: 978-1-60805-256-1, 2012
ISBN: 978-1-60805-520-3



Recommend this eBook to your Library

Indexed in: Book Citation Index, Science (BKCI-S), Web of Science, BIOSIS Previews, Scopus

Tumor development and progression are multi-factorial processes, in which genomic alterations and modifications in gene expression in ...[view complete introduction]

Table of Contents

Foreword

- Pp. i

Yinon Ben-Neirah

Download Free

Preface

- Pp. ii-iii (2)

Adit Ben-Baruch

Download Free

List of Contributors

- Pp. iv-vii (4)

Adit Ben-Baruch

Download Free

The Metastatic Microenvironment

- Pp. 3-13 (11)

Sivan Izraely and Isaac P. Witz

View Abstract Purchase Chapter

Tumor-Infiltrating Inflammatory Cells as Possible Therapeutic Targets

- Pp. 14-28 (15)

Paola Larghi, Chiara Porta, Elena Riboldi, Paola Allavena, Alberto Mantovani and Antonio Sica

View Abstract Purchase Chapter

TNF and Cancer: Friends and/or Foes?

- Pp. 29-56 (28)

Loris Bertazza, Simone Mocellin, Mark DeWitte and Donato Nitti

View Abstract Purchase Chapter

IL-1 is a Major Cytokine that Controls the Balance between Inflammation and Immunity in the Tumor Microenvironment

- Pp. 57-80 (24)

Ron N. Apte and Elena Voronov

View Abstract Purchase Chapter

ELR+ CXC Chemokines and their Role in Malignancy

- Pp. 81-87 (7)

Ellen C. Keeley, Borna Mehrad and Robert M. Strieter

View Abstract Purchase Chapter

The CXCR3/CXCR3 Ligand Axis: Friend or Foe?

- Pp. 88-98 (11)

Yanchun Li and Amy M. Fulton

View Abstract Purchase Chapter

The Inflammatory CC Chemokines CCL2 and CCL5 in Malignancy: Leukocyte Migration and Beyond

- Pp. 99-114 (16)

Adit Ben-Baruch

View Abstract Purchase Chapter

Homeostatic Chemokines

- Pp. 115-122 (8)

Amanda Burkhardt and Albert Zlotnik

View Abstract Purchase Chapter

Inflammation and Beyond: Complex Roles for TGF- β in the Tumor Microenvironment

- Pp. 123-154 (32)

Dror Luger and Lalage M. Wakefield

View Abstract Download Free

Microenvironmental Mediators as Therapeutic Targets in Malignancy

- Pp. 155-167 (13)

Amnon Peled

View Abstract Purchase Chapter

Index

- Pp. 168-173 (6)

Adit Ben-Baruch

Download Free

Foreword

Back in 1863 Rudolf Virchow, the founder of modern pathology, observed leukocytes nesting in neoplastic tissues ("lymphoreticular infiltrate" in his words). Consequently, he suggested that cancer may arise at sites of chronic irritation. This is how the link between inflammation and cancer was born. Hundred and fifty years later, cancer researches and pathologists have begun to appreciate the significance of the inflammation-cancer nexus. Even though a "lymphoreticular infiltrate" in tumors is often invisible, it is likely that inflammation plays a role in most tumors. However, it remained to determine whether inflammation in cancer is good for the patient and bad for the tumor, or vice versa. In this regard, we have witnessed in recent years a paradigm shift. The dogma prevailing until the turn of the 20th century was that inflammation and immunity play their classical protective role by defeating cancer like pathogens. This view was profoundly outlined in the "cancer immunosurveillance" theory formulated in 1957 by Burnet and Thomas. These two protagonists of the field proposed that lymphocytes act as sentinels in recognizing and eliminating nascent transformed cells that arise frequently in mammalian tissues. However, epidemiological, experimental and clinical evidence failed to support this notion. Numerous studies have demonstrated that immune-deficient humans and mice do not develop cancer at a higher frequency than their normal counterparts, yet, surprisingly, all these negative data only intensified the efforts to reinforce a cancer-debilitated immune system. Immuno-adjuvants, in vivo and ex-vivo immune stimulation by native or modified tumor cells and other attempts to mobilize the immune system in the fight against cancer have commonly failed. But these frustrating efforts have not been in vein. They cultivated novel and heretic trends, beginning by forsaking the cancer immunosurveillance theory and ending with the advancement of initially provocative views, implying that immunity and inflammation may inadvertently serve the tumor rather the host.

What have we learned recently about immunity and inflammation in cancer? We realized that inflammatory cells and cytokines at the tumor microenvironment are more likely to enhance, rather than curb tumor progression and may even induce local immunosuppression. We also understood that cancer susceptibility is often associated with functional polymorphism of pro-inflammatory cytokine genes, and that depriving the tumor of pro-inflammatory cytokines retards its progression in experimental models. A notable example is TNF, once perceived as its acronym stands for: tumor necrosis factor. Today, however, TNF is an outstanding example for a tumor promoting factor. Based on this rising evidence, Mantovani and Balkwill denoted cancer promoting mutations as "the match that lights the fire”, whereas inflammation, chemokine and cytokines would be the “fuel that feeds the flames”.

Hence, the time is ripe to review the mounting knowledge of cytokines and chemokines in the context of cancer and draw the insights required to harness this knowledge for cancer therapy. This eBook on “The Inflammatory Milieu of Tumors: Cytokines and Chemokines”, edited by Adit Ben-Baruch, is an important step in that direction. It provides an updated overview of tumor-infiltrating cells and soluble mediators, while highlighting their role in cancer. It also outlines intervention modes in experimental systems, aiming to turn the microenvironment against the tumor.

We have learned a great deal about the nature, sources and purpose of Virchow's "lymphoreticular infiltrate". The challenge of the future is to develop the means for taming the immune system to extinguish, rather than feed the deadly flames of cancer. Hopefully, readers of this eBook will gain ideas and insights as to how to cope with this challenge.

Yinon Ben-Neirah
The Lautenberg Center for Immunology and Cancer Research
The Hebrew University-Hadassah Medical School, Jerusalem
Israel


Preface

Tumor development and progression are multi-factorial processes, in which genomic alterations and modifications in gene expression in pre-malignant cells are joined by deleterious microenvironmental factors. The tumor milieu contains stroma cells and leukocytes, soluble factors and matrix components. The intensive interplay that exists between such host factors and the tumor cells plays a major role in dictating the final outcome of the malignant process.

Of the different microenvironmental factors that are present at the tumor milieu, much emphasis was recently given to inflammatory mediators. Inflammatory components may represent early efforts of the host to combat the arising tumor; however, failure to survey the developing tumor and inappropriate control of the inflammatory process may skew the inflammatory mediators into pro-malignancy factors. The inflammatory components support cell growth and invasion, induce mutagenesis, increase angiogenicity, and suppress potential anti-tumor immune functions.

Accordingly, extensive research that has been undertaken in the last several years has led to the current concept, suggesting that the inflammatory milieu in tumors is often overloaded with “enemies within”, that may be used by the malignant cells for their own benefit. The inflammatory constituents that prevail in tumors include leukocytes and soluble mediators. Of the different soluble factors, the focus was put on inflammatory cytokines and chemokines.

The aim of the present eBook is to provide in depth description of the roles played by inflammatory mediators in malignancy, and to set the basis for their consideration as therapeutic targets in cancer. The first seven chapters of the eBook describe the tumor microenvironment and its inflammatory components: cells, cytokines and chemokines. The next two chapters describe additional with important cytokines of the tumor microenvironment that are not directly connected to inflammation. The eBook concludes with a chapter describing the potential use of microenvironmental mediators as therapeutic targets in malignancy.

Specifically, the eBook begins by an introductory chapter, presenting the metastatic microenvironment (Chapter 1). This chapter exemplifies the important roles of the microenvironment in metastasis by discussing the large variety of components that contribute to brain metastases (Chapter 1). This chapter is followed by detailed description of the inflammatory microenvironment that prevails in many tumors (Chapter 2). Thus, Chapter 2 describes the cells participating in cancer-related inflammation, and also addresses the value of these cells, and of their products, as potential therapeutic targets in malignancy.

Chapter 3 and Chapter 4 discuss in a detailed manner two inflammatory cytokines that are present at the tumor microenvironment, tumor necrosis factor (TNF) and interleukin 1 (IL-1). Chapter 3 provides a very comprehensive overview of TNF in cancer biology, emphasizing the complex nature of the cytokine and of its doubled-edged effects, at the tumor milieu. Chapter 4 describes IL-1 as a key regulator of the balance between inflammation and immunity at the tumor microenvironment, and highlights the roles played by members of the IL-1 family in many aspects of the cancerous process.

The three next chapters are devoted to inflammatory chemokines in malignancy. In Chapter 5, the focus is put on the ELR-expressing CXC chemokines, describing the major roles of these factors in promoting angiogenesis. Contrasting the activities of the ELR-expressing CXC chemokines, the anti-angiogenic properties of non-ELR CXC chemokines that act through CXCR3, are discussed in Chapter 6. Chapter 6 also illuminates the controversial roles of these chemokines in cancer, manifested by their ability to control leukocyte infiltration to tumor sites and to regulate directly tumor-promoting properties in the tumor cells. This part of the eBook concludes with Chapter 7, in which the multifaceted roles of CC chemokines in malignancy are discussed. The chapter illustrates the pro-malignancy functions of the two chemokines, which are mediated by their roles as typical inducers of leukocyte motility, but also by regulating other malignancy-related functions.

Together, the above-mentioned chapters of the eBook emphasize the divergent functions of inflammatory cells and soluble mediators in malignancy. To provide a more comprehensive view of the tumor microenvironment, these chapters are followed by two chapters addressing additional components of the tumor milieu: the family of homeostatic chemokines (Chapter 8) and transforming growth factor ß (TGFß) (Chapter 9). The chapter on homeostatic chemokines (Chapter 8) describes the characteristics and functions of members of this functional sub-family of chemokines, including in malignancy. Chapter 9 provides a very broad and extensive discussion on the multiple roles of TGFß at the cancer microenvironment, discussing the challenging observations on its tumor-suppressive, alongside with tumor-promoting effects, in cancer.

Following these chapters, demonstrating the high complexity and combined activities of multiple cells and factors at the tumor milieu, Chapter 10 discusses the potential therapeutic implications of the different components that are found in proximity to the developing and metastasizing tumor cells, and describes work-in-progress that is performed in this respect.

Overall, the eBook provides an overview of the different components of the tumor microenvironment, and illustrates the roles played by inflammatory and non-inflammatory components in malignancy. The different chapters of the eBook emphasize the complexity of the cancer milieu, and the fact that often many of its elements are skewed to the pro-malignancy phenotype.

The topics addressed in the eBook are of interest to investigators who study basic aspects of the malignant process, to clinicians who wish to better understand the processes involved in malignancy, and to pharmacological companies that seek novel candidates for therapeutic intervention in cancer.

Adit Ben-Baruch
Department of Cell Research and Immunology
George S. Wise Faculty of Lift Sciences
Tel Aviv University
Israel

List of Contributors

Editor(s):
Adit B.-Baruch
Tel Aviv University
Israel




Contributor(s):
Sivan Izraely
Department of Cell Research and Immunology
George S. Wise Faculty of Life Sciences
Tel Aviv University
Tel Aviv
Israel


Isaac P. Witz
Department Cell Research and Immunology
George S. Wise Faculty of Life Sciences
Tel Aviv University
Tel Aviv, 69978
Israel


Paola Larghi
Istituto Clinico Humanitas
IRCCS, 20089 Rozzano
Milan
Italy


Chiara Porta
DISCAFF
University of Piemonte Orientale A. Avogadro
Novara, 28100
Italy


Elena Riboldi
DISCAFF
University of Piemonte Orientale A. Avogadro
Novara, 28100
Italy


Paola Allavena
Istituto Clinico Humanitas
IRCCS Milan
Rozzano, 20089
Italy


Alberto Mantovani
Istituto Clinico Humanitas
IRCCS Milan
Rozzano, 20089
Italy


Antonio Sica
Istituto Clinico Humanitas
IRCCS Milan
Rozzano, 20089
Italy


Loris Bertazza
Department of Oncological & Surgical Sciences
Section of Clinica Chirurgica 2 University of Padova
via Giustiniani 2
Padua, 35128
Italy


Simone Mocellin
Department of Oncological & Surgical Sciences
Section of Clinica Chirurgica 2 University of Padova
via Giustiniani 2
Padua, 35128
Italy


Mark DeWitte
Haematology / Oncology Clinical R&D CSL Ltd
45 Poplar Road Parkville
VIC, 3052
Australia


Donato Nitti
Department of Oncological & Surgical Sciences
Section of Clinica Chirurgica 2 University of Padova
via Giustiniani 2
Padua, 35128
Italy


Elena Voronov
Department of Microbiology and Immunology
University Ben Gurion of the Negev
Beer-Sheva, 84105
Israel


Ron N. Apte
The Shraga Segal Department of Microbiology and Immunology
Faculty of Health Sciences
Ben-Gurion University of the Negev
Beer-Sheva, 84105
Israel


Ellen C. Keeley
Department of Medicine
Division of Cardiology
University of Virginia
Charlottesville
Virginia
USA


Borna Mehrad
Departments of Medicine and Microbiology
Pulmonary and Critical Care Medicine
University of Virginia
Charlottesville
Virginia
USA


Robert M. Strieter
University of Virginia
Department of Medicine
Division of Pulmonary Critical Care, Box 800466
Charlottesville
Virginia , 22908-0466
USA


Yanchun Li
Marlene and Stewart Greenebaum Cancer Center and Department of Pathology
University of Maryl and School of Medicine
USA


Amy Fulton
Department of Pathology
University of Maryland, Greenebaum Cancer Center
University of Maryland, School of Medicine
9th Floor, 655 W. Baltimore St.
Baltimore
MD, 21201
USA


Adit Ben-Baruch
Department of Cell Research and Immunology
George S. Wise Faculty of Life Sciences
Tel Aviv University
Tel Aviv, 69978
Israel


Amanda Burkhardt
Department of Physiology and Biophysics
University of California Irvine
Irvine
CA, 92697
USA


Albert Zlotnik
Department of Physiology and Biophysics
University of California Irvine
Irvine
CA, 92697
USA


Dror Luger
Laboratory of Cancer Biology and Genetics
National Cancer Institute
Bethesda
MD, 20892
USA


Lalage M. Wakefield
Laboratory of Cancer Biology and Genetics
National Cancer Institute
Bethesda
MD, 20892
USA


Amnon Peled
Goldyne Savad Institute of Gene Therapy
Hadassah Hebrew University Hospital
P.O. Box 12000
Jerusalem, 91120
Israel




Advertisement

4th annual Immunogenicity


Webmaster Contact: info@benthamscience.org Copyright © 2017 Bentham Science