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Cytokines and their receptors comprise a critical communication pathway among the various cell types of the immune system that regulate cell growth, survival, differentiation, activation, and trafficking. As such, dysregulation of cytokine expression or secretion, cytokine-receptor expression, and their linked intracellular signaling pathways can result in undesired cell growth, survival, and ultimately malignant transformation. Use of transgenic mouse technology provides a powerful tool to better understand the physiologic sequelae resulting from unregulated activation of a cytokine/receptor pair at the level of the whole organism. In addition to altered expression of cytokine/receptor pairs leading directly to malignancy, indirect effects may also be elucidated using carcinogen models. Although other chapters in this book provide in depth review of individual cytokines’ role in the genesis or therapy of cancer, here we generally discuss transgenic and knock-out mouse models that lead to malignant transformation. When relevant, studies from patients with cancer are also mentioned to provide some correlation with human disease, in addition to other chapters in this volume. One common theme that emerges from these models is the importance of chronic cytokine-induced growth, survival, or inflammatory signals as a background leading to malignant transformation. Ultimately, better understanding of the cellular and molecular events that lead to the development of cancer will help provide novel targets for therapeutic intervention.

Cancer immunosurveillance has been debated for well over a century, but more recent experimental data over the past 15 years has clearly been supportive for an important role for cytokines and other effector molecules in host resistance to transformation . Importantly, this molecular biology era has brought with it the discovery of new hormones (cytokines such as IL-2 and interferons [IFNs]) and messengers (chemokines) that activate and direct leukocytes in a coordinated fashion. Clinical application quickly followed and immune cell/cytokine immunotherapies now herald the promise of new forms of cancer therapy. Cytokines have pivotal effects on the carcinogenic process. On the one hand they can be involved in the activation of immune effector mechanisms that limit the growth of the tumor, but on the other they may contribute to inflammation, transformation, tumor growth, invasion, and metastasis (as discussed in earlier chapters). Cytokines are produced by host stromal and immune cells, in response to molecules secreted by the tumor cells or as part of inflammation that frequently accompanies tumor growth. Tumor cells also produce cytokines in the same environment. How a local cytokine network operates in tumors is determined by the array of cytokines and receptors expressed and their relative concentrations. The net cytokine environment likely varies at various stages of tumor development.

In addition to their well-documented roles in leukemia and lymphoma, cytokines and chemokines can directly affect the progression of solid tumors, including carcinomas . Carcinomas are the most frequent human tumors that arise from the epithelial cells that line the inner surfaces of organs. The conversion of normal epithelial cell to metastatic tumor cell is accepted as a multi-stage process that requires progressive genetic alterations within the epithelial tumor cell and has been the focus of intense investigation over the past three decades . At the same time, the many other cell types in the tumor microenvironment are increasingly appreciated as components of a complex biologic network akin to an organ system that are critical for tumor progression, and thus may provide new targets for cancer therapy .

The term was first coined by John Hunter, a British surgeon, to describe blood vessel formation in reindeer antlers in 1787. The first histologic description of angiogenesis was presented by Arthur Tremain Hertig in 1935, detailing the formation of placental blood vessels. In 1939, based on observations of tumors transplanted to transparent chambers in in vivo animal models, A. G. Ide and colleagues proposed the existence of a tumor-derived factor capable of stimulating blood vessel formation . In 1945, G. H. Algire and his co-workers at the National Cancer Institute (NCI) recognized that the blood supply of tumors was derived from the host and was essential for tumor growth . The findings of Algire et al. offered the first evidence supporting the association between tumor vasculature and tumor growth. In 1948, I. C. Michaelson postulated that a diffusible angiogenic factor produced by the retina conferred the neovascularization phenotype observed during proliferative diabetic retinopathy and named this soluble factor as “Factor X” . Twenty years later, Greenblatt and Shubik and Ehrmann and Knoth demonstrated independently that tumor cells could stimulate vasoproliferation through transfilter diffusion experiments and confirmed the notion of a diffusible angiogenic factor elaborated by tumor cells. In 1971, Judah Folkman further refined the view on the relationship between tumor and its vasculature by hypothesizing that the growth of cancer from a few cell layers thick into a gross tumor requires angiogenic stimuli which are mediated by substances produced by the tumor. He proposed that anti-angiogenic therapy, therefore, might be an effective approach to treating human cancers . This view on tumor angiogenesis eas provocative and contrary to the prevailing thoughts of the time. Despite not being accepted by the scientific community, Dr. Folkman endeavored along this line of research and initiated the effort that lead to the isolation of the first angiogenic cytokine, basic fibroblast growth factor (bFGF) . Findings from his work have come to form the foundation in the molecular understanding of tumor angiogenesis and Dr. Folkman is often regarded as the “father of angiogenesis”.

Chemotactic cytokines (chemokines) are a family of small proteins (8–10 kDa) inducing directed cell migration (chemotaxis) along a chemical gradient . Chemokines tightly regulate the positioning of leukocytes in secondary lymphoid organs (e.g., in lymph nodes and thymus), and are key determinants of the recruitment of leukocytes at sites of inflammation and tumor tissues. Besides hematopoietic cells, chemokines affect several other cell types, such as epithelial and endothelial cells, fibroblasts and tumor cells. Chemokines play an important role in immune and inflammatory reactions; in addition most of these molecules affect other important cell functions such as angiogenesis, collagen production, activation of enzymes and regulation of cell growth and apoptosis. Forty-seven chemokines have been identified so far in man. Based on a cystein motif, different subfamilies: CXC, CC, C and CX3C have been classified (Table 1). The chemokine scaffold consists of an N-terminal loop connected via Cys bonds to the more structured core of the molecule (three b sheets) with a C terminal a helix .

Cachexia, or wasting, is the most common syndrome resulting from human malignancies, estimated to contribute to nearly a quarter of all cancer deaths. Although cachexia has been clinically diagnosed for more than a century, it is only relatively recently that investigators have begun unraveling the molecular mechanisms underlying the wasting state that predominates in adipose and skeletal muscle tissues. Tumor necrosis factor-α, or TNF-α is considered a leading mediator or cancer cachexia. This cytokine is produced by tumor, immune, and stromal cells to provide a growth and survival advantage within the tumor microenvironment. It also functions in an autocrine and paracrine fashion in adipose and skeletal muscles to regulate tissue breakdown. TNF-induced fat catabolism is largely regulated through the feeding response and through the control of gene expression to differentiate and maintain the homeostasis of adipose tissue. Regulation of skeletal muscle catabolism in cachexia is regulated by the ubiquitin-proteasome system, whose activity may also be controlled by TNF. Elucidation of the TNF signaling pathway has provided further insight into the regulation of cancer cachexia. One effector of this pathway in particular, NF-kB, appears to be essential for TNF-mediated fat and skeletal muscle decay. Understanding the mechanisms by which NF-kB functions in cancer cachexia may reveal still other novel therapeutic targets of wasting that may be used in combination with currently existing anti-TNF therapy.

IL-2 was originally isolated as a soluble factor with the property of enhancing T-lymphocyte proliferation in studies of the human immunodeficiency virus The earliest studies of its activity in the cellular therapy of cancer used partially-purified IL-2 from the Jurkat human T-cell line. Subsequent studies used recombinant IL-2 produced in , an unlimited source of this valuable cytokine that has been used more than any other immunologic agent for laboratory and clinical investigations of immunotherapy for malignant and nonmalignant disease. Proof of concept for the potent activity of IL-2-activated killer cells (termed lymphokine-activated killer, or LAK cells) against established malignancy in animal models was provided in the extensive series of reports from Rosenberg and the Surgery Branch of the National Cancer Institute beginning in the mid-1980s The earliest human studies used Jurkat-derived IL-2 and vivo-activated autologous LAK cells derived from leukapheresis of patients with advanced cancer. These patients initially received intravenous IL-2 before mononuclear cell collections and then received additional IL-2 following the re-infusion of autologous lymphocytes that had undergone further exposure to IL-2 for several days. The encouraging level of activity against renal cancer and melanoma, including a 5–7% rate of durable complete remission, was particularly gratifying in light of the marked resistance of these two malignancies to chemotherapy and other biologic agents such as interferon. Subsequent clinical trials demonstrated that exposure of patient cells to IL-2 was not necessary, as the in vivo exposure appeared to be associated with a comparable likelihood of antitumor response .At the same time, the success of this approach at centers outside of the National Cancer Institute was confirmed with a series of studies by the Cytokine Working Group and other institutions .

Although the ability of IL-2 to induce sustained tumor regression in patients with renal cell cancer and melanoma established a clinical role for cytokine therapy in fighting cancer, the severe toxicity seen in early trials limited its application to a select group of patients . In 1989 cytotoxic lymphocyte maturation factor, later termed IL-12, was discovered . IL-12 plays a central role in interferon gamma (IFN-γ) production and the development of a Th1 type immune response, thereby playing a role in both innate and adaptive immunity. In mouse models, IL-12 can inhibit tumor growth and metastasis. Early clinical trials of rhIL-12 in melanoma and renal cell cancer were complicated by severe toxicity and attenuation of the immune response over time. Revised dosing schedules, alternate routes of administration, and the use of combination cytokine therapy have led to improved tolerability and more sustained immune activation, but have resulted in only modest clinical activity. Current clinical trials continue to explore new ways to augment the antitumor activity of IL-12 in lymphoma and other potentially responsive malignancies.

Interferon-α2 (IFN-α2) has been tested extensively in human clinical trials and has proven to confer a survival benefit to patients with melanoma, renal cell carcinoma (RCC), chronic myelogenous leukemia (CML), hemangioma and various other malignancies. To date, the precise molecular determinants that differentiate responders from nonresponders have not been defined. A majority of the current knowledge about IFN-α2 has been derived from its role as an endogenously-produced antiviral compound. Importantly, new information on the activity of exogenously administered IFN-α is beginning to emerge as a result of its widespread use for tumor immunotherapy. This chapter will focus on the biology of IFN-α and its effects on downstream signaling events within the tumor cell and host immune effectors. We will highlight both endogenous and exogenous IFNα2, because information from each might provide insight into the mechanism of action of IFNα as an immunotherapeutic agent. Continued research on the basic biology of the IFN system could potentially lead to a greater understanding of its antitumor activity and greater clinical benefit while reducing its toxic side effects.

Cytokines represent a diverse group of small, soluble polypeptides that are involved in regulating a wide range of physiologic processes, including inflammation, tissue repair, and immunity. The expanding role of cytokines in these processes and the identification of over 100 putative cytokine family members have made it difficult to easily classify cytokines based on structure or function. In addition, many cytokines exhibit a variety of biologic activities and these effects may be dependent on the concentration, timing, and duration of target cell exposure to a given cytokine, as well as the influence of other cytokine and growth factors in the local microenvironment. In fact, much of the early characterization of cytokines was based on simple in vitro experiments, which have failed to accurately predict the activity of cytokines in vivo. More recent investigation using targeted knockout mice and analysis of cytokine signaling pathways is leading to new insights into the biology of many cytokines. This is perhaps best exemplified by interleukin-2 (IL-2), originally described as a T-cell growth factor and defined by its ability to induce T-cell proliferation in vitro. Such ex vivo studies predicted that IL-2 would function to promote cellular immunity through expansion of naive T-cell populations in vivo. The availability of IL-2 and IL-2 receptor knockout mice, however, demonstrated that in the absence of IL-2 signaling T-cell proliferation was increased, significant lymphadenopathy occurred, and animals succumb to aggressive autoimmune disease. This unexpected result suggests that IL-2 may actually function in vivo, not as a T-cell stimulant, but rather as a regulatory cytokine maintaining peripheral tolerance through balancing effector and regulatory T-cell pools .