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A05: Function of the receptor for advanced glycation end products (RAGE) in inflammation-associated
liver carcinogenesis

Chronic tissue damage and inflammation is a main driver of cancer development and progression. Human hepatocellular carcinoma (HCC) arises preferentially at sites of chronic liver injury, accompanied by sustained inflammation, hepatocyte cell death and compensatory proliferation. Both tumor cell-specific alterations as well as the establishment of a pro-tumorigenic microenvironment, which has an impact on the tumor compartment, play an essential role; hence, an attractive strategy for innovative anti-cancer therapy is the specific inhibition of key regulators coordinating an active microenvironment. There is accumulating evidence that activation of receptor of advanced glycation end products (RAGE) signaling pathways in the liver could contribute to the developme nt and progression of numerous types of hepatic disorders, including steatosis and fibrosis, and hepatocellular carcinoma (HCC) growth and metastasis. Indeed, we have shown that ablation of Rage impairs inflammation-associated tumorigenesis and delays the onset of liver damage and fibrosis. Importantly, we identified signaling pathways initiated by RAGE as key events in regulating hepatic progenitor cell activation. In the proposed project, we will analyze RAGE in hepatic progenitor cells (known as oval cells in the mouse) in murine models of progenitor cell activation as well as inflammation-associated liver carcinoge esis. The major goals of our project are: i) determine the role of RAGE in progenitor cell activation for HCC development, ii) to use RAGE ligands responsible for progenitor cell activation to identify the downstream RAGE-dependent genetic programs in these cells supporting HCC development, and iii) comparison with data from human liver pathologies including HCC to unravel new targets for intervention in chronic liver tissue damage and carcinogenesis.

Publications

Dropmann A, Dediulia T, Breitkopf-Heinlein K, Korhonen H, Janicot M, Weber SN, Thomas M, Piiper A, Bertran E, Fabregat I, Abshagen K, Hess J, Angel P, Coulouarn C, Dooley S, Meindl-Beinker NM (2016) TGF-β1 and TGF-β2 abundance in liver diseases of mice and men. Oncotarget 7(15):19499- 518
De Ponti A, Wiechert L, Pusterla T, Longerich T, Hogg N, Vogel A, Schirmacher P, Hess J, Angel P (2015) A pro-tumorigenic function of S100A8/A9 in carcinogen-induced hepatocellular carcinoma. Cancer Lett 369(2):396-404.
De Ponti A, Wiechert L, Stojanovic A, Longerich T, Marhenke S, Hogg N, Vogel A, Cerwenka A Schirmacher P, Hess J, Angel P (2014) Chronic liver inflammation and hepatocellular carcinogenesis are independent of S100A9. Int J Cancer 136(10):2458-63.
Horwitz E, Stein I, Andreozzi M, Nemeth J, Shoham A, Pappo O, Schweitzer N, Tornillo L, Kanarek N, Quagliata L, Zreik F, Porat RM, Finkelstein R, Reuter H, Koschny R, Ganten T, Mogler C, Shibolet O, Hess J, Breuhahn K, Grunewald M, Schirmacher P, Vogel A, Terracciano L, Angel P, Ben-Neriah Y, Pikarsky E (2014) Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to sorafenib treatment. Cancer Discov 4:730-743.
Pusterla T, Nemeth J, Stein I, Wiechert L, Knigin D, Marhenke S, Longerich T, Kumar V, Arnold B, Vogel A, Bierhaus A, Pikarsky E, Hess J, Angel P (2013) Receptor for advanced glycation end products (RAGE) is a key regulator of oval cell activation and inflammation-associated liver carcinogenesis in mice. Hepatology 58:363-373.
Leibold JS, Riehl A, Hettinger J, Durben M, Hess J, Angel P (2013) Keratinocyte-specific deletion of the receptor RAGE modulates the kinetics of skin inflammation in vivo. J Invest Dermatol 133(10):2400-6.
Wiechert L, Nemeth J, Pusterla T, Bauer C, De Ponti A, Manthey S, Marhenke S, Vogel A, Klingmuller U, Hess J, Angel P (2012) Hepatocyte-specific S100a8 and S100a9 transgene expression in mice causes Cxcl1 induction and systemic neutrophil enrichment. Cell Commun Signal 10:40.
Riehl, A, Bauer T, Brors B, Busch H, Mark R, Nemeth J, Gebhardt C, Bierhaus A, Nawroth P, Eils R, Konig R, Angel P*, Hess J (2010) Identification of the Rage-dependent gene regulatory network in a mouse model of skin inflammation. BMC Genomics 11:537. *corresponding author
Nemeth J, Stein I, Haag D, Riehl A, Longerich T, Horwitz E, Breuhahn K, Gebhardt C, Schirmacher P, Hahn M, Ben-Neriah Y, Pikarsky E, Angel P*, Hess J (2009) S100A8 and S100A9 are novel nuclear factor kappa B target genes during malignant progression of murine and human liver carcinogenesis. Hepatology 50:1251-1262. *corresponding author
Gebhardt C, Riehl A, Durchdewald M, Németh J, Fürstenberger G, Müller-Decker K, Enk A, Arnold B, Bierhaus A, Nawroth PP, Hess J, Angel P (2008) RAGE signaling sustaines inflammation and promotes tumor development. J Exp Med 205:275-85.