Untersuchungen zur differentiellen Bedeutung des Immunsystems für die Hepatokarzinogenese
Principal Investigator: Dr. Arndt Vogel
Tumors often arise at sites of inflammation and chronic inflammation is increasingly recognized to be important in the pathogenesis of many malignancies. Each stage of malignancies appears to be exquisitely susceptible to regulation of immune cells. Activation of the adaptive immune system in response to tumors might result in eradication of malignant cells. On the other hand, immune cells, which infiltrate tumors and preneoplastic lesions, produce a variety of cytokines and chemokines that propagate a localized inflammatory response and that can also enhance the growth and survival of premalignant cells. Hepatocellular carcinoma, which is one of the most lethal and prevalent cancers worldwide, represents a classic case of inflammation-linked cancer. There is increasing evidence indicating that the immune system contributes to heptocarcinogenesis. Understanding the molecular mechanisms underlying the tumor promoting properties of the immune system is critical to any effort to slow down hepatocarcinogenesis by either bolstering antitumor responses or by neutralizing cancer promoting properties of immune cells. The aim of our study is to define the role of the immune system for tumor development in the liver during chronic injury. Our longterm aim is to find novel treatment strategies through pharmacologic activation or inactivation of key oncogenic pathways to prevent or at least delay liver tumor development.
- El Serag, H.B., Marrero, J.A., Rudolph, L., and Reddy, K.R. 2008. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology 134:1752-1763.
- de Visser, K.E., Eichten, A., and Coussens, L.M. 2006. Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6:24-37.
- He, G., Yu, G.Y., Temkin, V., Ogata, H., Kuntzen, C., Sakurai, T., Sieghart, W., Peck-Radosavljevic, M., Leffert, H.L., and Karin, M. Hepatocyte IKKbeta/NF-kappaB Inhibits Tumor Promotion and Progression by Preventing Oxidative Stress-Driven STAT3 Activation. Cancer Cell 17:286-297.
- Balkwill, F., and Mantovani, A. 2001. Inflammation and cancer: back to Virchow? Lancet 357:539-545.
- Chan, A.T., Ogino, S., and Fuchs, C.S. 2007. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med 356:2131-2142.
- Maeda, S., Kamata, H., Luo, J.L., Leffert, H., and Karin, M. 2005. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121:977-990.
- Luedde, T., Beraza, N., Kotsikoris, V., van Loo, G., Nenci, A., De Vos, R., Roskams, T., Trautwein, C., and Pasparakis, M. 2007. Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 11:119-132.
- Pikarsky, E., Porat, R.M., Stein, I., Abramovitch, R., Amit, S., Kasem, S., Gutkovich-Pyest, E., Urieli-Shoval, S., Galun, E., and Ben-Neriah, Y. 2004. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431:461-466.
- Swann, J.B., and Smyth, M.J. 2007. Immune surveillance of tumors. J Clin Invest 117:1137-1146.
- Shankaran, V., Ikeda, H., Bruce, A.T., White, J.M., Swanson, P.E., Old, L.J., and Schreiber, R.D. 2001. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410:1107-1111.
- Grivennikov, S.I., Greten, F.R., and Karin, M. Immunity, Inflammation, and Cancer. Cell 140:883-899.
- de Visser, K.E., Korets, L.V., and Coussens, L.M. 2005. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7:411-423.
- Tumanov, A.V., Koroleva, E.P., Christiansen, P.A., Khan, M.A., Ruddy, M.J., Burnette, B., Papa, S., Franzoso, G., Nedospasov, S.A., Fu, Y.X., et al. 2009. T cell-derived lymphotoxin regulates liver regeneration. Gastroenterology 136:694-704 e694.
- Strick-Marchand, H., Masse, G.X., Weiss, M.C., and Di Santo, J.P. 2008. Lymphocytes support oval cell-dependent liver regeneration. J Immunol 181:2764-2771.
- Haybaeck, J., Zeller, N., Wolf, M.J., Weber, A., Wagner, U., Kurrer, M.O., Bremer, J., Iezzi, G., Graf, R., Clavien, P.A., et al. 2009. A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell 16:295-308.