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review series

Figure 2 Signal transduction pathways and major biological responses of inflammation-modulating cytokines in cancer. The signaling pathways shown can control tumor development through a direct effect on tumor cells (e.g., NF-kB, STAT3, and caspases) and/or an indirect effect on immune and endothelial cells (e.g., NF-kB, STAT3, STAT4, and SMAD). DR4, death receptor 4; FADD, Fas-associated death domain; gp130, glycoprotein 130; TRADD, TNF receptor–associated death domain protein; TRAF2, TNF receptor–associated factor 2; TYK2, tyrosine kinase 2.

apoptosis (41). This finding could explain why recurrent infec- tions promote the progression of MM (41).

This Review focuses on the role of various cytokines produced by innate immune cells on tumor development and progression. The cytokines to be discussed include TNF-α, TRAIL, IL-6, IL-17, IL-12, IL-23, IL-10, and TGF-β (Figure 2). As mentioned above, these cytokines can promote and/or inhibit tumor development. The involvement of chemokines in chronic inflammation–associated tumor progression will not be covered in this Review.

TNF-α The critical role of TNF-α in chronic inflammatory diseases is well established (43), and its tumor-promoting effects have been dem- onstrated (44). TNF-α produced by tumor cells or inflammatory cells in the tumor microenvironment can promote tumor cell sur- vival through the induction of genes encoding NF-kB–dependent antiapoptotic molecules (39) (Figures 2 and 3). In asbestos-induced human malignant mesothelioma, macrophages phagocytose asbes- tos and then release TNF-α. This TNF-α promotes cell survival and thereby reduces asbestos-induced cytotoxicity, increasing the pool of asbestos-damaged mesothelial cells that are susceptible to malig- nant transformation (45). TNF-α has also been proposed to con- tribute to tumor initiation by stimulating the production of geno- toxic molecules, that is, molecules that can lead to DNA damage and mutations, such as NO and ROS (4). Genetic polymorphisms that enhance TNF-α production are associated with increased risk of MM, bladder cancer, hepatocellular carcinoma (HCC), gas- tric cancer, and breast cancer, as well as poor prognosis in various hematological malignancies (44). Other actions of TNF-α that might enhance tumor progression, as opposed to tumor initiation, include promotion of angiogenesis and metastasis, as well as impair- ment of immune surveillance by strongly suppressing many T cell responses and the cytotoxic activity of activated macrophages (46).

Studies have suggested a role for keratinocyte-produced TNF-α in mouse models of skin carcinogenesis (47, 48). Skin cancer induction by administration of the carcinogen 7,12-di- methylbenz[a]anthracene (DMBA) and tumor promoters results in much higher tumor incidence in TNF-α–sufficient mice than TNF-α–deficient mice (47). Reduced tumorigenesis was also found in mice deficient in both the TNF-α receptors TNFR1 and TNFR2 (48). A tumor-promoting role for TNF-α has also been found in cholestatic liver cancer, which develops as a result of chronic liver inflammation in mice lacking the drug and phospholipid transporter MDR2 (49). Treatment with TNF-αspecific neutralizing antibody during the tumor promotion stage resulted in apoptosis of transformed hepatocytes and a failure to progress to HCC. An important role for TNF-α in the promotion phase of HCC has also been suggested (50). In that study, TNF-α expression was upregulated during liver stem cell proliferation induced by a choline-deficient and ethionine- supplemented diet. Liver stem cell proliferation and tumori- genesis were found to depend on TNFR1. Yet another study has indicated that TNF-α signaling is crucial for promoting liver metastasis of a colon adenocarcinoma line (51). In another tumor transplantation model of cancer, LPS administration to tumor-bearing mice induced production of TNF-α and stimu- lated metastatic tumor growth in the lung (39). Taken together, proinflammatory TNF-α released by host and tumor cells is an important factor involved in initiation, proliferation, angiogen- esis, and metastasis of various types of cancers.

TRAIL The TNF superfamily member TRAIL can bind five different receptors, two of which, death receptor 4 (DR4) and DR5, have cytoplasmic death domains that deliver caspase-dependent apoptotic signals to the cell on which they are expressed (52).

The Journal of Clinical Investigation

http://www.jci.org

Volume 117

Number 5

May 2007

1177

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