The mixture of cytokines that is produced in the cancer microenvironment has an important role in cancer pathogenesis. Cytokines that are released in response to infection, inflammation and immunity can function to inhibit cancer development and progression. Alternatively, cancer cells can respond to host-derived cytokines that promote growth, attenuate apoptosis and facilitate invasion and metastasis.
Cytokines are released in response to a diverse range of cellular stresses, including carcinogen-induced injury, infection and inflammation. In these settings, cytokines function to stimulate a host response that is aimed at controlling the cellular stress and minimizing cellular damage. Whereas effective containment of the insult promotes tissue repair, the failure to resolve the injury can lead to persistent cytokine production and to an exacerbation of tissue destruction. As such, host reactions to cellular stress can impact on several stages of cancer formation and progression.(table 1)
Table 1: Cytokines (endogenous) in cancer pathogenesis
|Cytokines||Role in cancer formation|
|Il-1||Required for tumor invasion and angiogenesis|
|IL-6||Required for chemically induced lymphomas|
|IL-12||Inhibits chemical carcinogenesis|
|IL-15||Promotes natural killer T cell leukaemias|
|IFN-γ||Inhibits chemical carcinogenesis; Inhibits lymphomas; Stat1 and Rag2 inhibit carcinomas|
|M-CSF||Promotes breast cancer invasion|
|GM-CSF||Inhibits lymphomas and carcinomas|
|TNF-α||Required for chemically-induced skin cancer|
|MIF||Inhibits p53 tumor-suppressor functions|
|TGF-β||Inhibits colon carcinomas|
|Fas-Fas ligand||Inhibits lymphomagenesis|
Inflammatory conditions in some tissues increase the risk of cancer. Cytokines and chemokines are components of an intensive dialog promoting angiogenesis, metastasis, subversion of adaptive immunity and changing response to hormones and to chemotherapeutic agents. Cytokines involved in cancer-related inflammation represent a target for innovative diagnostic and therapeutic strategies, and a future challenge for scientists and clinicians.(figure1)
Studies on TNF demonstrating enhancement of cancer cell invasion ability, provided early proof for a pro-tumor function of inflammatory cytokines. TNF-mediated tumor promotion can involve different pathways: a direct effect on tumor cells of low concentration of this cytokine; an interplay with the chemokine system with induction of CXCR4; stimulation of epithelial to mesenchymal transition. These findings have constituted the necessary background for the development of clinical protocols employing TNF antagonists in cancer therapy.
IL-1 was shown to augment metastasis, a finding which at the time was related to induction of adhesion molecules in target organs. In a pancreatic islet tumor model, a first wave of myc-driven angiogenesis is induced by the inflammatory cytokine IL-1. In an unexpected twist, IL-1α was also shown recently to play a pivotal role in the pathogenesis of liver cancer. Recent studies have uncovered a novel relationship between sex steroid hormones and cancer. In carcinoma of the prostate, an androgen-dependent cancer, sensitivity to hormonal stimula-tion is regulated by selective androgen receptor modulators (SARM). The inflammatory cytokine IL-1 produced by macrophages in the tumor microenvironment converts SARMs from inhibitors to stimulators.
IL-6 is a key growth-promoting and antiapoptotic inflammatory cytokine and is also one of the effector signals of activated NF-κB in the promotion of neoplasia. A clear pro-tumoral role for IL-6 has been demonstrated in multiple myeloma (MM) where both an autocrine loop of IL-6 produc-tion as well as a paracrine loop by bone marrow stromal cells have been reported.
Human patients with colon cancer produce high levels of IL-6. Hepatocellular carcinoma (HCC), the most common type of liver cancer, is a frequent outcome after years of chronic inflammation, induced either by chronic infection (HBV, HCV) or sustained alcohol consumption. IL-6 serum levels in these patients at risk of HCC are usually elevated. Also in the breast cancer IL-6 play a key role because the presence of specific polymorphism in IL-6 promoter region and consequently high levels of IL-6 is a predisposing genetic factor that contributes to breast cancer worse prognosis.
The tumor microenvironment is generally characterized by high concentration of immunosuppressive cytokines IL-10 and TGF-β. In advanced neoplasia there is usually low level of IL-12 and defective activation of conventional Th1 immunity. Recent genetic evidence indicates that the IL-12-related cytokine IL-23 promotes skin carcinogenesis. IL-23 promotes the differentiation of Th17 cells which orchestrates neutrophil-initiated resistance to extracellular bacteria and inflammation. TGF-βis a tumor suppressor frequently involved in human tumors and associated with metastasis, though it can also act under certain conditions as a tumor promoter. In a mammary carcinoma model, deficiency in the type II TGF-β receptor is associated with metastasis and recruitment of MDSC. The chemokines CXCL5 and CXCL12, acting on the chemokine receptors CXCR2 and CXCR4, respectively, mediate MDSC recruitment. MDSC facilitate metastasis via metalloproteinase activity. Interestingly, chemokine-mediated recruitment in TGF-β RII-deficient tumors was associated with increased levels of TGF-β1.
Chemokines have long been associated with the recruitment of leukocytes in tumors. Recent results with gene targeted mice have provided unequivocal evidence for a role of CC chemokines in carcinogenesis.
The contribution of chemokines to angiogenesis and tumor pro-motion has been the object of intensive investigation. A variety of chemokines, including CCL2, CXCL12, CXCL8, CXCL1, CXCL13, CCL5, CCL17, and CCL22, have been detected in neoplastic tissues as products of either tumor cells or stromal elements. CXCL1 and re-lated molecules [CXCL2, CXCL3, CXCL8, or interleukin-8 (IL-8)] have an important role in melanoma progression by stimulating neoplastic growth, promoting inflammation, and inducing angio-genesis. Strong evidence demonstrates that levels of CCL2 are associated with TAM accumulation and that CCL2 may play an important role in the regulation of angiogenesis. Expression of chemokine receptors plays an important role in guiding metastasis. Up-regulation of CXCR4 is downstream the Von Hippel Lindau activation of tyrosine kinase oncogenes and TNF. CXCR4 is the most frequently up-regulated chemokine receptor in cancer cells and it is associated with advanced stages and metastasis.
Numerous pre-clinical studies established the ability of cytokine-secreting cancers to function as cellular vaccines that augment systemic immunity against wild-type cancers. Several strategies have been pursued to translate this form of immunotherapy into clinical testing. One approach uses autologous cancer cells, as experiments in mouse models indicate that cancer-specific antigens might be the most potent for cancer vaccination. The logistical challenges in preparing patient-specific therapies, however, have motivated the exploration of ALLOGENEIC cancer cell lines. These express shared cancer antigens and can be phagocytosed and processed by host DCs through cross-priming. Using these approaches, many cytokines have been introduced into early-stage clinical trials, including GM-CSF, IL-2, IL-4, IL-6, IL-7, IL-12, IFN- γ and lymphotactin.(table2)
Table 2: Cytokines as cancer therapy
|Il-2||Enhances NK cell and CD8 T cell function; increases vascular permeabilty|
|IL-3||Enhances cancer antigen presentation|
|IL-4||Enhances eosinophil function and T-cell activation|
|IL-6||Enhances T-cell and B-cell function; inhibition of IL-6 reduces lymphoproliferation|
|IL-7||Enhances T-cell function|
|IL-10||Inhibits cancer antigen presentation|
|IL-12||Enhances Th1 immunity and cytotoxicity; anhibits angiogensis|
|IL-13||Inhibits cytotoxicity against viral neoplasms|
|IL-18||Enhances Th1 immunity and cytotoxicity; inhibits angiogenesis|
|M-CSF||Enhances macrophage function|
|GM-CSF||Enhances cancer antigen presentation|
|IFN-α||Enhances cancer antigen presentation and cytotoxicity|
|IFN-γ||Enhances cancer antigen presentation and cytotoxicity|
|TNF-α||Induces tumor-cell apoptosis; activates andothelium and granulocytes|
|TRAIL||Induces tumor-cell apoptosis|
|FLT3 ligand||Stimulates dendritic-cell and NK-cell function|
|Lymphotactin||Enhances T-cell recruitment|
|TGF-β||Inhibits T-cell effector function|