Cannabinoid receptor 1 promotes hepatocellular carcinoma initiation and progression through multiple mechanisms

Liver canceris the third most prevalent cancer with 695,000 deaths worldwide (1). The American Cancer Society’s estimates for 2013 are about 30,640 new cases of liver cancerin the United States and about 21,670 deaths from these cancers. (2). The 5-year survival rate of individuals with liver canceris only 8.9% despite aggressive conventional therapy, marking this malignancy the second most lethal after pancreatic cancer (3). Hepatocellular carcinoma ( HCC) is the most common type of liver cancerand it accounts for 4 out of 5 liver tumors. The most common underlying factor is cirrhosis caused by viral hepatitis, chronic alcoholism or obesity (4, 5), although HCCcan also develop in the absence of cirrhosis. Most treatments are inadequate and there is also a lack of biomarkers for early diagnosis of HCC. Diethylnitrosamine (DEN)-induced liver cancerin mice is the most widely used animal model of HCC, with a gene expression profile similar to that in a subset of human HCCwith low survival (6). The near 100% effectiveness of DEN treatment to induce HCCwith a reproducible time-course has made this model uniquely suited to analyze mechanisms of HCC. Endocannabinoids are lipid mediators that interact with the same G protein-coupled receptors – CB1R and CB2R – that mediate the effects of the psychoactive ingredient of marijuana, Δ9-tetrahydrocannabinol. CB1R expression is very high in the brain and much lower yet functionally relevant in peripheral tissues including the liver, whereas CB2R expression is restricted primarily to immune and hematopoietic cells (7). Activation of hepatic CB1R stimulates de novo lipogenesisand induces hepatic insulin resistance (7, 8), and their expression is induced by chronic alcohol intake, high-fat diets and liver fibrosis (9–11), conditions known to predispose to cirrhosis and HCC. Hyperactivationof the biosynthesis of the endocannnabinoid anandamideand induction of CB1R following partial hepatectomy in mice contribute to the early stages of liver regenerationvia inducing key cell cycle proteins involved in mitotic progression, such as FOXM1(12). FOXM1is also upregulated in HCCand contributes to tumor progression and various aspects of tumorogenesis (13), and CB1R is induced in HCC(14). Such observations suggest a functional link between the endocannabinoid/CB1R system and FOXM1in the development and progression of HCC. We explored the possible such a functional link by monitoring the development and growth of DEN-induced HCCin wild-type mice treated with vehicle or a peripheral CB1R antagonist as well as in CB1R−/− mice. Furthermore, we identified tumor-induced, CB1R-mediated changes in hepatic gene expression by analyzing the transcriptome of normal and cancerous liver tissue from individuals with HCCand from wild-type and CB1R−/− mice. The results highlight the role of CB1R in inducing multiple tumor promoting pathways, including the Gi/o/CREBP/ FOXM1/Bin1/IDO2 ( indoleamine 2,3-dioxygenase2) pathway that promotes tumor immune tolerance.