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.