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review series

TGF-β TGF-β, like IL-10, is not only a powerful pleiotropic immunosup- pressive and antiinflammatory cytokine but also a central regula- tor in Treg proliferation and function (Figure 3) (113–115). TGF-β signals mainly through activation of SMAD transcription factors, but it also leads to MAPK activation (Figure 2) (116, 117). Defec- tive TGF-β signaling due to mutational inactivation of the type 2 TGF-β receptor (TβRII) has been found to occur frequently in human colon cancer (118, 119), where TGF-β potently inhibits the growth of colon epithelial cells (117). Such mutations occur at the adenoma-to-carcinoma transition or at a later stage, indicat- ing that the tumor suppressor effect of TGF-β is mainly critical at late stages of colon carcinogenesis (120). In addition to direct tumor suppressor activity on colon epithelial cells and antiinflam- matory effects on T cells, TGF-β has been implicated in Treg-medi- ated suppressive activity (114). SMAD3 is a key mediator of the antiinflammatory and immunosuppressive activities of TGF-β in the colon (121). Accordingly, both TGF-β1– and SMAD3-deficient mice exhibit increased colon carcinogenesis that depends on the presence of certain enteric bacteria, possibly H. hepaticus (122, 123); germ-free Tgfb1–/– and Smad3–/– mice do not develop colon cancer when H. hepaticus is no longer present (122, 123). Interestingly, TGF-β signaling prevents the release of IL-6 from Th1 cells during the late stages of CAC and therefore functions to control tumor growth (66). Conversely, IL-6–activated STAT3 signaling counter- acts the TGF-β–mediated cytostatic effect through induction of inhibitory SMAD7 (124).

invasion, and metastasis (117). Such invasive action of TGF-β has been well documented in mouse models of skin carcinomas (117). In addition, both TGF-β–induced changes in the microen- vironment, to favor angiogenesis, and inhibition of tumor-specific CD8+ T cells promote tumor development (Figure 3) (117, 125). In summary, the complex role of TGF-β in tumor suppression and progression might be stage and cancer cell type dependent.

Conclusions The evidence reviewed in this Review demonstrates that activa- tion of innate immunity and inflammation results in the pro- duction of cytokines that can either stimulate or inhibit tumor growth and progression. By and large, most proinflammatory cytokines produced by either host immune cells or tumor cells themselves promote tumor development. By contrast, proapop- totic (TRAIL) and antiinflammatory (IL-10 and TGF-β) cytokines usually interfere with tumor development. These findings pro- vide a unique therapeutic opportunity based on selective inter- ference with the action of proinflammatory and tumor-promot- ing cytokines while enhancing the activity of proapoptotic and antiinflammatory cytokines. In addition to selective modulation of cytokine signaling, interfering with NF-kB activation in tumor cells can further prevent the pro-survival and growth-promoting effects of proinflammatory cytokines such as TNF-α and render the cancer cells more susceptible to elimination by proapoptotic cytokines such as TRAIL.

Despite its pronounced antiinflammatory activity and growth inhibition of early tumor cells, TGF-β might also enhance tumor progression. Carcinomas often secrete excess TGF-β and respond to it by enhanced epithelial-to-mesenchymal transition, tissue

Address correspondence to: Michael Karin, University of Cali- fornia, San Diego, 9500 Gilman Drive #0723, La Jolla, California 92093-0723, USA. Phone: (858) 534-1361; Fax: (858) 534-8158; E-mail: karinoffice@ucsd.edu.

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The Journal of Clinical Investigation


Volume 117

Number 5

May 2007


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