The anti-tumorigenic role of the cannabinoid receptor 2 in colon cancer

The endocannabinoid system consists of the activation of differentially expressed cannabinoid receptors by endogenous ligands. Cannabinoid receptor 2 (CB2) is a known immunomodulator predominantly expressed in immune cells. Its role in cancer remains controversial as CB2 expression has been associated with cancer severity whereas CB2 agonists demonstrated anti-proliferative and pro-apoptotic actions in cancer cells. To elucidate the causal role of CB2 in cancer, we used CB2 knockout (CB2^-/-) mice. In aging CB2^-/- mice we observed a higher incidence of spontaneous precancerous lesions in multiple organs, including the colon and reproductive organs, compared to wildtype controls. We then investigated the anti-tumorigenic role of CB2 in colon cancer using the AOM/DSS model of colitis-associated colorectal cancer and a model for hereditary colon cancer (Apc^Min/+). CB2 knockout in AOM/DSS-treated female mice resulted in higher disease activity assessed by colonoscopy, aggravated colonic shortening, and increased number of dysplastic polyps and tumors of all sizes. Similarly, compared to Apc^Min/+CB2^+/+ mice, Apc^Min/+CB2^-/- mice showed more aggressive cancer development in male and female mice. Mice lacking the CB2 receptor in both models of colon cancer showed enhanced splenic populations of immunosuppressive cells, specifically myeloid derived suppressor cells, and a decrease in anti-tumor CD8+ T cells, suggesting that CB2 activation suppresses colon cancer development by altering the balance between pro-tumorigenic and anti-tumorigenic immune cells. Finally, we found corroborative genomic data in a large human population (UK BioBank) indicating a significant association between non-synonymous variants of CNR2 and colon cancer incidence in humans.