Chapter Eight - Cytokine Regulation of Metastasis and Tumorigenicity

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Abstract

The human body combats infection and promotes wound healing through the remarkable process of inflammation. Inflammation is characterized by the recruitment of stromal cell activity including recruitment of immune cells and induction of angiogenesis. These cellular processes are regulated by a class of soluble molecules called cytokines. Based on function, cell target, and structure, cytokines are subdivided into several classes including: interleukins, chemokines, and lymphokines. While cytokines regulate normal physiological processes, chronic deregulation of cytokine expression and activity contributes to cancer in many ways. Gene polymorphisms of all types of cytokines are associated with risk of disease development. Deregulation RNA and protein expression of interleukins, chemokines, and lymphokines have been detected in many solid tumors and hematopoetic malignancies, correlating with poor patient prognosis. The current body of literature suggests that in some tumor types, interleukins and chemokines work against the human body by signaling to cancer cells and remodeling the local microenvironment to support the growth, survival, and invasion of primary tumors and enhance metastatic colonization. Some lymphokines are downregulated to suppress tumor progression by enhancing cytotoxic T cell activity and inhibiting tumor cell survival. In this review, we will describe the structure/function of several cytokine families and review our current understanding on the roles and mechanisms of cytokines in tumor progression. In addition, we will also discuss strategies for exploiting the expression and activity of cytokines in therapeutic intervention.

Introduction

The human body responds to biological stresses such as tissue injury or infection through the remarkable process of inflammation. Inflammation is characterized by the mobilization of immune cells, induction of angiogenesis, and alterations in the connective tissue, all of which result in tissue repair or clearance of the pathogen. The inflammatory process, which occurs in complex organisms such as mammals, birds, and reptiles (Montali, 1988), was first observed in injured tissues by London surgeon Dr. John Hunter who lived from 1728 until 1793 (Turk, 1994). Acute inflammation occurs during normal physiological functions such as wound healing of infection, and is defined as short term (Collins et al., 2014, Pullamsetti et al., 2011). Disease conditions such as allergic disorders, autoimmune diseases, and cancer are characterized by chronic inflammation resulting in the destruction of normal tissues (Izuhara and Harada, 1993, Jin et al., 1989, Konaka et al., 1981, Stahl et al., 1994). Cancer is often referred to as “wounds that do not heal” due to signs of chronic inflammation such as angiogenesis, recruitment of macrophages, and accumulation of fibroblasts (Dvorak, 2015).

Inflammatory responses are regulated by a broad class of soluble proteins termed cytokines (5–20 kDa). Based on function, cell target, and structure, cytokines are subdivided into several categories: interleukins, chemokines, and lymphokines. Interleukins are known for their ability to modulate immune cell activity, including proliferation, maturation, and migration (Skopinska & Ziembikiewicz, 1978). Chemokines are termed for their ability to stimulate directed cell migration (chemotaxis) (Deuel et al., 1981). Lymphokines are characterized by their secretion from lymphocytes and are subdivided into several molecular families that include: interferons, tumor necrosis factor (TNF), and transforming growth factors (Haber et al., 1972, Kehrl et al., 1986, Williamson et al., 1983). Early identification of cytokines relied on experimentation of blood-derived factors in cell culture and in chick cam studies (Cantell, 1961, Isaacs et al., 1958, Lockart et al., 1962). Genomics, proteomics, and bioinformatics technologies will continue to advance the discovery of new cytokines.

The expression and activity of cytokines are deregulated in many cancer types, contributing to chronic inflammation. Emerging studies indicate that interleukins, chemokines, and lymphokines play functionally redundant as well as distinct roles in order to sustain tumor growth, survival, and invasion. In the following sections, we will focus on the role of particular cytokines in the primary tumor and metastatic niche, highlighting advances in our understanding of how these cytokines modulate tumor progression. Furthermore, we will discuss the progress and challenges of utilizing our knowledge of cytokine biology to develop effective anticancer therapies. In this way, we hope this review will be informative to those who seek up to date information on the role of cytokines in tumorigenesis and metastasis.

Section snippets

Interleukins

Interleukins were initially discovered through studies on the pathogenesis of fever. They were described as secreted factors from leukocytes (lymphocytes), which regulated intercommunication among cells, thus giving rise to its current name. These early studies showed that interleukins regulated lymphocyte proliferation in response to antigenic stimuli (de Weck et al., 1979, Farrar et al., 1980). While interleukins were thought be primarily expressed by lymphocytes, interleukins are expressed

Chemokines

Chemokines were first discovered as a class of proteins that direct the migration of neutrophils and monocytes through the formation of concentration gradients (Locati et al., 1994, Sozzani et al., 1991). Since then, chemokines are known to recruit other immune cell types including T cells and natural killer (NK) cells, and also act on mesenchymal cells to promote angiogenesis during inflammation. Chemokines encompass a large family of proteins (5–10 kDa) in which over 40 ligands and 16

Chemokines in Therapy

Current literature indicates that C–C and C–X–C chemokines modulate the primary tumor and metastatic microenvironments by signaling to cancer cells, and recruitment of stromal cells including endothelial cells, bone marrow-derived cells, and Th2 cells (Fig. 6). Given the importance of chemokine signaling in cancer progression, there is a great deal of interest in developing new therapies targeting chemokine ligands or receptors. A number of chemokine ligand and receptor antagonists are

Interferons

Interferons (IFNs) are homodimeric soluble proteins in the cytokine class that were originally named for their ability to interfere with viral replication inside host cells. There are three types of IFNs: I, II, and III. Type I IFNs consist of interferon alpha (IFN-α) and interferon beta (IFN-β). Type II IFN consists of IFN-γ. The most recently discovered type of IFNs is type III IFN (IFN-λ). Upon recognition of a pathogen—be it viral, bacterial, fungal, or tumor cells—various host cells will

Tumor Necrosis Factor

The cytokine TNF is notable for its long history in cancer research. About 100 years ago, the New York surgeon William Coley developed a cancer treatment with a mixture of bacteria products called “Coley's toxin,” which stimulated patient responses (Aggarwal, Gupta, & Kim, 2012). Subsequent efforts led to the discovery of a factor that was induced in patients with bacterial infections (Carswell et al., 1975). Furthermore, this factor induced tumor necrosis when injected into several animal

Closing Remarks

This review has focused on multiple families of cytokines including: interleukins, chemokines, interferons, and TNF. These cytokines appear to play distinct and overlapping roles in regulating tumor progression, by signaling to cancer cells and remodeling the tumor microenvironment. Ongoing clinical trials demonstrate mixed results for delivering tumor suppressive cytokines such as interferons and targeting tumor promoting cytokines such as chemokines. Studies indicate that exploiting cytokine

References (567)

  • K.P. Bhat et al.

    Mesenchymal differentiation mediated by NF-kappaB promotes radiation resistance in glioblastoma

    Cancer Cell

    (2013)
  • A.E. Bigildeev et al.

    Leukemia cells invading the liver express liver chemokine receptors and possess characteristics of leukemia stem cells in mice with MPD-like myeloid leukemia

    Experimental Hematology

    (2011)
  • P. Biswas et al.

    Interleukin-6 induces monocyte chemotactic protein-1 in peripheral blood mononuclear cells and in the U937 cell line

    Blood

    (1998)
  • J.G. Bode et al.

    Hepatic acute phase proteins—Regulation by IL-6- and IL-1-type cytokines involving STAT3 and its crosstalk with NF-kappaB-dependent signaling

    European Journal of Cell Biology

    (2012)
  • L. Borsi et al.

    Selective targeted delivery of TNFalpha to tumor blood vessels

    Blood

    (2003)
  • H. Bozcuk et al.

    Tumour necrosis factor-alpha, interleukin-6, and fasting serum insulin correlate with clinical outcome in metastatic breast cancer patients treated with chemotherapy

    Cytokine

    (2004)
  • K. Brocke-Heidrich et al.

    Interleukin-6-dependent gene expression profiles in multiple myeloma INA-6 cells reveal a Bcl-2 family-independent survival pathway closely associated with Stat3 activation

    Blood

    (2004)
  • J.A. Burger et al.

    CXCR4: A key receptor in the crosstalk between tumor cells and their microenvironment

    Blood

    (2006)
  • L. Cabal-Hierro et al.

    TRAF-mediated modulation of NF-kB AND JNK activation by TNFR2

    Cellular Signalling

    (2014)
  • S.H. Chang et al.

    Signaling of interleukin-17 family cytokines in immunity and inflammation

    Cellular Signalling

    (2011)
  • L. Chang et al.

    The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover

    Cell

    (2006)
  • F. Charni et al.

    Syndecan-1 and syndecan-4 are involved in RANTES/CCL5-induced migration and invasion of human hepatoma cells

    Biochimica et Biophysica Acta

    (2009)
  • X. Chen et al.

    Increased IL-17-producing cells correlate with poor survival and lymphangiogenesis in NSCLC patients

    Lung Cancer

    (2010)
  • X.S. Cheng et al.

    CCL20 and CXCL8 synergize to promote progression and poor survival outcome in patients with colorectal cancer by collaborative induction of the epithelial-mesenchymal transition

    Cancer Letters

    (2014)
  • W.L. Cheng et al.

    Overexpression of CXCL1 and its receptor CXCR2 promote tumor invasion in gastric cancer

    Annals of Oncology

    (2011)
  • H.J. Cho et al.

    Low serum interleukin-6 levels as a predictive marker of recurrence in patients with hepatitis B virus related hepatocellular carcinoma who underwent curative treatment

    Cytokine

    (2015)
  • F. Clatot et al.

    Intratumoural level of SDF-1 correlates with survival in head and neck squamous cell carcinoma

    Oral Oncology

    (2011)
  • A. Collado-Hidalgo et al.

    Cytokine gene polymorphisms and fatigue in breast cancer survivors: Early findings

    Brain, Behavior, and Immunity

    (2008)
  • P. Abe et al.

    Intermediate progenitors facilitate intracortical progression of thalamocortical axons and interneurons through CXCL12 chemokine signaling

    The Journal of Neuroscience

    (2015)
  • K. Abiko et al.

    IFN-gamma from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer

    British Journal of Cancer

    (2015)
  • W. Abushahba et al.

    Antitumor activity of type I and type III interferons in BNL hepatoma model

    Cancer Immunology, Immunotherapy

    (2010)
  • M. Agarwal et al.

    CCL11 (eotaxin-1): A new diagnostic serum marker for prostate cancer

    Prostate

    (2013)
  • C.M. Ahmed et al.

    IFN-gamma and its receptor subunit IFNGR1 are recruited to the IFN-gamma-activated sequence element at the promoter site of IFN-gamma-activated genes: Evidence of transactivational activity in IFNGR1

    Journal of Immunology

    (2006)
  • A. Aiuti et al.

    The chemokine SDF-1 is a chemoattractant for human CD34 + hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34 + progenitors to peripheral blood

    The Journal of Experimental Medicine

    (1997)
  • Y. Akishima-Fukasawa et al.

    Prognostic significance of CXCL12 expression in patients with colorectal carcinoma

    American Journal of Clinical Pathology

    (2009)
  • R. Albulescu et al.

    Cytokine patterns in brain tumour progression

    Mediators of Inflammation

    (2013)
  • K. Aleksandrova et al.

    Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer

    Hepatology

    (2014)
  • A. Almofti et al.

    The clinicopathological significance of the expression of CXCR4 protein in oral squamous cell carcinoma

    International Journal of Oncology

    (2004)
  • J.L. Ambrus et al.

    Free interferon-alpha/beta receptors in the circulation of patients with adenocarcinoma

    Cancer

    (2003)
  • A.M. Aragay et al.

    Monocyte chemoattractant protein-1-induced CCR2B receptor desensitization mediated by the G protein-coupled receptor kinase 2

    Proceedings of the National Academy of Sciences of the United States of America

    (1998)
  • D.A. Arenberg et al.

    Inhibition of interleukin-8 reduces tumorigenesis of human non-small cell lung cancer in SCID mice

    The Journal of Clinical Investigation

    (1996)
  • J.M. Arnold et al.

    Reduced expression of chemokine (C-C motif) ligand-2 (CCL2) in ovarian adenocarcinoma

    British Journal of Cancer

    (2005)
  • T. Ashizawa et al.

    Clinical significance of interleukin-6 (IL-6) in the spread of gastric cancer: Role of IL-6 as a prognostic factor

    Gastric Cancer

    (2005)
  • R. Attar et al.

    Association of CCL2 and CCR2 gene variants with endometrial cancer in Turkish women

    In Vivo

    (2010)
  • N. Au-Yeung et al.

    Transcriptional regulation by STAT1 and STAT2 in the interferon JAK-STAT pathway

    JAK-STAT

    (2013)
  • M. Awane et al.

    NF-kappa B-inducing kinase is a common mediator of IL-17-, TNF-alpha-, and IL-1 beta-induced chemokine promoter activation in intestinal epithelial cells

    Journal of Immunology

    (1999)
  • T. Bachelot et al.

    Prognostic value of serum levels of interleukin 6 and of serum and plasma levels of vascular endothelial growth factor in hormone-refractory metastatic breast cancer patients

    British Journal of Cancer

    (2003)
  • H. Bai et al.

    CCL5 secreted from bone marrow stromal cells stimulates the migration and invasion of Huh7 hepatocellular carcinoma cells via the PI3K-Akt pathway

    International Journal of Oncology

    (2014)
  • L. Bai et al.

    Genetic single-nucleotide polymorphisms of inflammation-related factors associated with risk of lung cancer

    Medical Oncology

    (2013)
  • E. Balentien et al.

    Effects of MGSA/GRO alpha on melanocyte transformation

    Oncogene

    (1991)
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