The role of the endocannabinoid system in hepatocarcinogenesis: investigation of chemically and genetically induced hepatocarcinogenesis in FAAH, CB1 and CB2 knockout mice.

• Applicant: Professor Dr. Ingmar Mederacke
• Subject Area: Gastroenterology
• Term: from 2010 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 189968933

Hepatocellular carcinoma (HCC) is the fifth most common cancer world-wide causing more than 500,000 deaths every year. Moreover, a rising incidence of HCC has been reported over the last three decades. Based on the involvement of endocannabinoids in the promotion of hepatic steatosis and fibrosis which are both associated with an increased risk for HCC development, we seek to investigate the potential contribution of the endocannabinoid system to hepatic carcinogenesis. The proposed experiments focus on three key regulators of the endocannabinoid system, the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH), cannabinoid receptor CB1 and cannabinoid receptor CB2. The potential contribution of endocannabinoids will be first tested in FAAH-deficient mice, which display 10-fold elevated levels of the endocannabinoid anandamide, using chemical and genetic models of HCC (Aim 1). The contribution of endcannabinoid receptors to hepatocarcinogenesis will be tested in CB1- and CB2-knockout mice as well as CB1-FAAH- and CB2-FAAH-double knockout mice (Aim 2). The cell type through which endocannabinoids and their receptors modulate hepatocarcinogenesis will be defined using CB1- and CB2-bone marrow chimeric mice, as well as mice with a conditional deletion of CB1 in hepatocytes, macrophages or hepatic stellate cells (Aim 3). The proposed experiments will not only promote our understanding of signaling pathways in hepatic carcinogenesis but may also serve as basis for novel treatment strategies.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Robert F. Schwabe