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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.

    • 1.

      Hanahan, D., and Weinberg, R.A. 2000. The hall- marks of cancer. Cell. 100:57–70.

    • 2.

      Coussens, L.M., and Werb, Z. 2002. Inflammation and cancer. Nature. 420:860–867.

    • 3.

      Shacter, E., and Weitzman, S.A. 2002. Chronic inflammation and cancer. Oncology. 16:217–226.

    • 4.

      Hussain, S.P., Hofseth, L.J., and Harris, C.C. 2003. Radical causes of cancer. Nat. Rev. Cancer. 3:276–285.

    • 5.

      Fox, J.G., and Wang, T.C. 2007. Inflammation, atro- phy, and gastric cancer. J. Clin. Invest. 117:60–69. doi:10.1172/JCI30111.

    • 6.

      Dobrovolskaia, M.A., and Kozlov, S.V. 2005. Inflammation and cancer: when NF-kappaB amal- gamates the perilous partnership. Curr. Cancer Drug argets. 5:325–344.

    • 7.

      de Visser, K.E., Eichten, A., and Coussens, L.M.

        • 2006.

          Paradoxical roles of the immune system dur- ing cancer development. Nat. Rev. Cancer. 6:24–37.

    • 8.

      Balkwill, F., Charles, K.A., and Mantovani, A. 2005. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell. 7:211–217.

    • 9.

      Karin, M., and Greten, F.R. 2005. NF-kB: linking inflammation and immunity to cancer development and progression. Nat. Rev. Immunol. 5:749–759.

  • 10.

    Karin, M. 2006. Nuclear factor-kB in cancer devel- opment and progression. Nature. 441:431–436.

  • 11.

    Luster, A.D., Alon, R., and von Andrian, U.H. 2005. Immune cell migration in inflammation: pres- ent and future therapeutic targets. Nat. Immunol. 6:1182–1190.

  • 12.

    Balkwill, F., and Mantovani, A. 2001. Inflammation and cancer: back to Virchow? Lancet. 357:539–545.

  • 13.

    Mantovani, A., Sozzani, S., Locati, M., Allavena,

      • P.

        , and Sica, A. 2002. Macrophage polarization: tumor-associated macrophages as a paradigm for

polarized M2 mononuclear phagocytes. Trends Immunol. 23:549–555.

  • 14.

    Ben-Baruch, A. 2006. Inflammation-associated immune suppression in cancer: the roles played by cytokines, chemokines and additional mediators. Semin. Cancer Biol. 16:38–52.

  • 15.

    Smyth, M.J., Cretney, E., Kershaw, M.H., and Hay- akawa, Y. 2004. Cytokines in cancer immunity and immunotherapy. Immunol. Rev. 202:275–293.

  • 16.

    Kim, R., Emi, M., Tanabe, K., and Arihiro, K. 2006. Tumor-driven evolution of immunosuppressive networks during malignant progression. Cancer Res. 66:5527–5536.

  • 17.

    Hadden, J.W. 2003. Immunodeficiency and cancer: prospects for correction. Int. Immunopharmacol. 3:1061–1071.

  • 18.

    Luo, J.L., Kamata, H., and Karin, M. 2005. IKK/ NF-kB signaling: balancing life and death-a new approach to cancer therapy. J. Clin. Invest. 115:2625–2632. doi:10.1172/JCI26322.

  • 19.

    Karin, M., Cao, Y., Greten, F.R., and Li, Z.W. 2002. NF-kB in cancer: from innocent bystander to major culprit. Nat. Rev. Cancer. 2:301–310.

  • 20.

    Karin, M. 2006. NF-and cancer: mechanisms and targets. Mol. Carcinog. 45:355–361.

  • 21.

    Pidgeon, G.P., et al. 1999. The role of endotoxin/ lipopolysaccharide in surgically induced tumour growth in a murine model of metastatic disease. Br. J. Cancer. 81:1311–1317.

  • 22.

    Taketomi, A., et al. 1997. Circulating intercellular adhesion molecule-1 in patients with hepatocel- lular carcinoma before and after hepatic resection. Hepatogastroenterology. 44:477–483.

  • 23.

    Medzhitov, R. 2001. Toll-like receptors and innate immunity. Nat. Rev. Immunol. 1:135–145.

  • 24.

    Akira, S., Uematsu, S., and Takeuchi, O. 2006.

Pathogen recognition and innate immunity. Cell. 124:783–801.

  • 25.

    Fritz, J.H., Ferrero, R.L., Philpott, D.J., and Girardin,

    • S.

      E. 2006. Nod-like proteins in immunity, inflam- mation and disease. Nat. Immunol. 7:1250–1257.

  • 26.

    Robinson, M.J., Sancho, D., Slack, E.C., Leibund- gut-Landmann, S. and Sousa, C.R. 2006. Myeloid C-type lectins in innate immunity. Nat. Immunol. 7:1258–1265.

  • 27.

    Klesney-Tait, J., Turnbull, I.R., and Colonna, M.

      • 2006.

        The TREM receptor family and signal inte- gration. Nat. Immunol. 7:1266–1273.

  • 28.

    Han, J., and Ulevitch, R.J. 2005. Limiting inflam- matory responses during activation of innate immunity. Nat. Immunol. 6:1182–1189.

  • 29.

    Staib, F., et al. 2005. The p53 tumor suppressor network is a key responder to microenvironmen- tal components of chronic inflammatory stress. Cancer Res. 65:10255–10264.

  • 30.

    Sun, J., et al. 2006. Interactions of sequence variants in interleukin-1 receptor-associated kinase 4 and the toll-like receptor 6-1-10 gene cluster increase prostate cancer risk. Cancer Epidemiol. Biomarkers Prev. 15:480–485.

  • 31.

    Hugot, J.P., et al. 2001. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 411:599–603.

  • 32.

    Podolsky, D.K. 2002. Inflammatory bowel disease.

    • N.

      Engl. J. Med. 347:417–429.

  • 33.

    Eckmann, L., and Karin, M. 2005. NOD2 and Crohn’s disease: Loss or gain of function? Immunity. 22:661–667.

  • 34.

    Sehouli, J., Mustea, A., Konsgen, D., Katsares, I., and Lichtenegger, W. 2002. Polymorphism of IL-1 receptor antagonist gene: role in cancer. Anticancer Res. 22:3421–3424.

The Journal of Clinical Investigation


Volume 117

Number 5

May 2007


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