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Background  There is good evidence in the literature that the cannabinoid system is disturbed in colorectal cancer. In the present study, we have investigated whether CB 1  receptor immunoreactive intensity (CB 1 IR intensity) is associated with disease severity and outcome.    Methodology/Principal Findings  CB 1 IR was assessed in formalin-fixed, paraffin-embedded specimens collected with a consecutive intent during primary tumour surgical resection from a series of cases diagnosed with colorectal cancer. Tumour centre (n = 483) and invasive front (n = 486) CB 1 IR was scored from 0 (absent) to 3 (intense staining) and the data was analysed as a median split i.e. CB 1 IR <2 and ≥2. In microsatellite stable, but not microsatellite instable tumours (as adjudged on the basis of immunohistochemical determination of four mismatch repair proteins), there was a significant positive association of the tumour grade with the CB 1 IR intensity. The difference between the microsatellite stable and instable tumours for this association of CB 1 IR was related to the CpG island methylation status of the cases. Cox proportional hazards regression analyses indicated a significant contribution of CB 1 IR to disease-specific survival in the microsatellite stable tumours when adjusting for tumour stage. For the cases with stage II microsatellite stable tumours, there was a significant effect of both tumour centre and front CB 1 IR upon disease specific survival. The 5 year probabilities of event-free survival were: 85±5 and 66±8%; tumour interior, 86±4% and 63±8% for the CB 1 IR<2 and CB 1 IR≥2 groups, respectively.    Conclusions/Significance  The level of CB 1  receptor expression in colorectal cancer is associated with the tumour grade in a manner dependent upon the degree of CpG hypermethylation. A high CB 1 IR is indicative of a poorer prognosis in stage II microsatellite stable tumour patients.

High Tumour Cannabinoid CB1 Receptor Immunoreactivity Negatively Impacts Disease-Specific Survival in Stage II Microsatellite Stable Colorectal Cancer