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Opposite roles of cannabinoid receptors 1 and 2 in hepatocarcinogenesis
  1. Ki-Tae Suk1,2,
  2. Ingmar Mederacke1,3,
  3. Geum-Youn Gwak1,4,
  4. Sung Won Cho5,
  5. Adebowale Adeyemi1,
  6. Richard Friedman6,
  7. Robert F Schwabe1,7
  1. 1Department of Medicine, Columbia University, New York, New York, USA
  2. 2Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea
  3. 3Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
  4. 4Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
  5. 5Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea
  6. 6Department of Biomedical Informatics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA
  7. 7Institute of Human Nutrition, Columbia University, New York, New York, USA
  1. Correspondence to Dr Robert F Schwabe, Department of Medicine, Columbia University, 1150 St. Nicholas Avenue, Russ Berrie Pavilion, Room 415, New York, NY 10032, USA; rfs2102{at}


Objective 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.

Design 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.

Results 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.

Conclusions Similar to their role in fibrogenesis, CB1 and CB2 exert opposite effects on hepatocarcinogenesis and may provide novel therapeutic targets.

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