Abstract
BackgroundThere is good evidence in the literature that the cannabinoid system is disturbed in colorectal cancer. In the present study, we have investigated whether CB1 receptor immunoreactive intensity (CB1IR intensity) is associated with disease severity and outcome.Methodology/Principal FindingsCB1IR 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) CB1IR was scored from 0 (absent) to 3 (intense staining) and the data was analysed as a median split i.e. CB1IR <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 CB1IR intensity. The difference between the microsatellite stable and instable tumours for this association of CB1IR was related to the CpG island methylation status of the cases. Cox proportional hazards regression analyses indicated a significant contribution of CB1IR 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 CB1IR 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 CB1IR<2 and CB1IR≥2 groups, respectively.Conclusions/SignificanceThe level of CB1 receptor expression in colorectal cancer is associated with the tumour grade in a manner dependent upon the degree of CpG hypermethylation. A high CB1IR is indicative of a poorer prognosis in stage II microsatellite stable tumour patients.
Highlights
The G-protein coupled cannabinoid1 (CB1) receptors are most well known for their role in mediating the psychotropic effects sought after by recreational users of cannabis
We found that at a dilution of 1:300, CB1 receptor immunoreactivity (CB1IR) was found in the epithelial cells of the crypts, with scattered positivity in subepithelial inflammatory cells (Fig. S1A), a finding consistent with studies of CB1IR in the normal colon [5,6]
The present study was motivated by data from both cultured cells and patient samples suggesting that a dysfunctional endocannabinoid signalling system is involved either in the pathogenesis and/or as a consequence of colorectal cancer [13,14,17,21,22]
Summary
The G-protein coupled cannabinoid (CB1) receptors are most well known for their role in mediating the psychotropic effects sought after by recreational users of cannabis. In addition to the functions described above, the endocannabinoid system acts as a ‘‘damage limiting’’ system to mitigate the effects of pathological situations. This appears to be true for the gastrointestinal endocannabinoid system. Aberrant crypt foci in the colon, an early pathological change in the adenomacarcinoma sequence in colorectal cancer development, are formed as a result of azoxymethane treatment in mice, and the treatment is associated with an increase in the levels of 2-arachidonoylglycerol. We have investigated whether CB1 receptor immunoreactive intensity (CB1IR intensity) is associated with disease severity and outcome
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