Chapter Eight - Cytokine Regulation of Metastasis and Tumorigenicity
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
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