title: Opposite roles of cannabinoid receptors 1 and 2 in hepatocarcinogenesis.
abstract: The endocannabinoid system (ECS) exerts key roles in the development of liver fibrosis and fatty liver, two diseases that promote the development of hepatocellular carcinoma (HCC). Although cannabinoids exert potent antitumour effects in vitro, the contribution of the ECS to carcinogenesis in vivo remains elusive.
  
  
  
  Expression of key components of the ECS, including endocannanabinoids, endocannabinoid-degrading enzymes and endocannabinoid receptors, was determined in healthy liver and tumours. Diethylnitrosamine-induced hepatocarcinogenesis was determined in mice deficient in fatty acid amide hydrolase (FAAH), the main anandamide (AEA)-degrading enzyme, in cannabinoid receptor (CB)1, CB2, or transient receptor potential cation channel subfamily V member 1 (TRPV1)-deficient mice.
  
  
  
  Murine and human HCCs displayed activation of the ECS with strongly elevated expression of CB1 and CB2 but only moderately altered endocannabinoid levels. Contrary to the antitumour effects of cannabinoids in vitro, we observed increased hepatocarcinogenesis in FAAH-deficient mice, a mouse model with increased AEA levels. Accordingly, inactivation of CB1, the main receptor for AEA, in wild-type or FAAH-deficient mice suppressed hepatocarcinogenesis. In contrast, inactivation of CB2 increased hepatocarcinogenesis. CB1 was strongly expressed within HCC lesions and its inactivation suppressed proliferation and liver fibrosis. CB2 was predominantly expressed in macrophages. CB2 inactivation decreased the expression of T-cell-recruiting chemokines and inhibited hepatic T-cell recruitment including particular CD4+ T cells, a population with known antitumour effects in HCC. TRPV1 deletion did not alter HCC development.
  
  
  
  Similar to their role in fibrogenesis, CB1 and CB2 exert opposite effects on hepatocarcinogenesis and may provide novel therapeutic targets.
authors.affiliation: Department of Medicine, Columbia University, New York, New York, USA Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea.
authors.forename: Ki-Tae
authors.identifier: 0000-0002-9206-9245
authors.initials: KT
authors.lastname: Suk
authors.affiliation: Department of Medicine, Columbia University, New York, New York, USA Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Ingmar
authors.initials: I
authors.lastname: Mederacke
authors.affiliation: Department of Medicine, Columbia University, New York, New York, USA Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Geum-Youn
authors.initials: GY
authors.lastname: Gwak
authors.affiliation: Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea.
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Cho
authors.affiliation: Department of Medicine, Columbia University, New York, New York, USA.
authors.forename: Adebowale
authors.initials: A
authors.lastname: Adeyemi
authors.affiliation: Department of Biomedical Informatics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Friedman
authors.affiliation: Department of Medicine, Columbia University, New York, New York, USA Institute of Human Nutrition, Columbia University, New York, New York, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Schwabe
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D063388:Endocannabinoids / Q000145:classification / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D043884:Receptor, Cannabinoid, CB1 / Q000032:analysis; D043885:Receptor, Cannabinoid, CB2 / Q000032:analysis / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D063388:Endocannabinoids; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2
keywords: FIBROSIS; HEPATOCELLULAR CARCINOMA; INFLAMMATORY MECHANISMS; LIVER