TY - JOUR
T1 - The Anti-Tumorigenic Role of Cannabinoid Receptor 2 in Colon Cancer
T2 - A Study in Mice and Humans
AU - Iden, Jennifer Ana
AU - Raphael-Mizrahi, Bitya
AU - Awida, Zamzam
AU - Naim, Aaron
AU - Zyc, Dan
AU - Liron, Tamar
AU - Kasher, Melody
AU - Livshits, Gregory
AU - Vered, Marilena
AU - Gabet, Yankel
N1 - Publisher Copyright:
© 2023 by the authors.
PY - 2023/2
Y1 - 2023/2
N2 - The endocannabinoid system, particularly cannabinoid receptor 2 (CB2 in mice and CNR2 in humans), has controversial pathophysiological implications in colon cancer. Here, we investigate the role of CB2 in potentiating the immune response in colon cancer in mice and determine the influence of CNR2 variants in humans. Comparing wild-type (WT) mice to CB2 knockout (CB2−/−) mice, we performed a spontaneous cancer study in aging mice and subsequently used the AOM/DSS model of colitis-associated colorectal cancer and a model for hereditary colon cancer (ApcMin/+). Additionally, we analyzed genomic data in a large human population to determine the relationship between CNR2 variants and colon cancer incidence. Aging CB2−/− mice exhibited a higher incidence of spontaneous precancerous lesions in the colon compared to WT controls. The AOM/DSS-treated CB2−/− and ApcMin/+CB2−/− mice experienced aggravated tumorigenesis and enhanced splenic populations of immunosuppressive myeloid-derived suppressor cells along with abated anti-tumor CD8+ T cells. Importantly, corroborative genomic data reveal a significant association between non-synonymous variants of CNR2 and the incidence of colon cancer in humans. Taken together, the results suggest that endogenous CB2 activation suppresses colon tumorigenesis by shifting the balance towards anti-tumor immune cells in mice and thus portray the prognostic value of CNR2 variants for colon cancer patients.
AB - The endocannabinoid system, particularly cannabinoid receptor 2 (CB2 in mice and CNR2 in humans), has controversial pathophysiological implications in colon cancer. Here, we investigate the role of CB2 in potentiating the immune response in colon cancer in mice and determine the influence of CNR2 variants in humans. Comparing wild-type (WT) mice to CB2 knockout (CB2−/−) mice, we performed a spontaneous cancer study in aging mice and subsequently used the AOM/DSS model of colitis-associated colorectal cancer and a model for hereditary colon cancer (ApcMin/+). Additionally, we analyzed genomic data in a large human population to determine the relationship between CNR2 variants and colon cancer incidence. Aging CB2−/− mice exhibited a higher incidence of spontaneous precancerous lesions in the colon compared to WT controls. The AOM/DSS-treated CB2−/− and ApcMin/+CB2−/− mice experienced aggravated tumorigenesis and enhanced splenic populations of immunosuppressive myeloid-derived suppressor cells along with abated anti-tumor CD8+ T cells. Importantly, corroborative genomic data reveal a significant association between non-synonymous variants of CNR2 and the incidence of colon cancer in humans. Taken together, the results suggest that endogenous CB2 activation suppresses colon tumorigenesis by shifting the balance towards anti-tumor immune cells in mice and thus portray the prognostic value of CNR2 variants for colon cancer patients.
KW - cannabinoid receptor 2
KW - colon cancer
KW - endocannabinoid system
KW - immunomodulation
KW - myeloid-derived suppressor cells
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85149026921&partnerID=8YFLogxK
U2 - 10.3390/ijms24044060
DO - 10.3390/ijms24044060
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C2 - 36835468
AN - SCOPUS:85149026921
SN - 1661-6596
VL - 24
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 4
M1 - 4060
ER -
