The Endocannabinoid System Protects against Colon Cancer Development Via CB2

Endocannabinoids are endogenous ligands that bind to the differentially expressed cannabinoid receptors. Cannabinoid receptor 2 (CB2) is predominantly expressed in immune and bone cells. Evidence from both in vitro and in vivo studies has established diametric roles of CB2 in inflammation and cancer. To elucidate the determinant role of the endocannabinoid system and specifically that of endogenous CB2 agonists in cancer, we used CB2 knockout (CB2^-/-) mice. We found higher incidence of spontaneous precancerous lesions in multiple organs, including the colon, in aging CB2^-/- mice. We then investigated if the CB2 receptor attenuates tumorigenesis in colon cancer using multiple approaches. Firstly, we compared wildtype to CB2^-/- mice receiving multi-stage chemical colorectal cancer induction using azoxymethane/dextran sodium sulfate (AOM/DSS) in female mice for 11 weeks. Secondly, we used a mouse strain with a genetic predisposition to intestinal adenomas (Apc^Min/+) and compared Apc^Min/+CB2^-/- to Apc^Min/+CB2^+/+ mice. For mice receiving AOM/DSS, we found that the CB2^-/- mice had higher disease activity assessed using colonoscopy, increased presence of dysplastic polyps, and a higher number of tumors. Additionally, compared to Apc^Min/+CB2^+/+ mice, Apc^Min/+CB2^-/- mice displayed increased colonic shortening and larger and increased number of tumors in the small and large intestine: we also observed enhanced splenic population of immunosuppressive and tumor-promoting cells called granulocytic-myeloid derived suppressor cells, and a decrease in anti-tumor CD8+ T cells. Taken together, these results suggest that endogenous CB2 activation suppresses colon cancer development likely by altering the balance between pro-tumorigenic and anti-tumorigenic immune cells.