Muscarinic Acetylcholine Receptor M3 Expression and Survival in Human Colorectal Carcinoma—An Unexpected Correlation to Guide Future Treatment?

Abstract

Muscarinic acetylcholine receptor M3 (M3R) has repeatedly been shown to be prominently expressed in human colorectal cancer (CRC), playing roles in proliferation and cell invasion. Its therapeutic targetability has been suggested in vitro and in animal models. We aimed to investigate the clinical role of MR3 expression in CRC for human survival. Surgical tissue samples from 754 CRC patients were analyzed for high or low immunohistochemical M3R expression on a clinically annotated tissue microarray (TMA). Immunohistochemical analysis was performed for established immune cell markers (CD8, TIA-1, FOXP3, IL 17, CD16 and OX 40). We used Kaplan–Meier curves to evaluate patients’ survival and multivariate Cox regression analysis to evaluate prognostic significance. High M3R expression was associated with increased survival in multivariate (hazard ratio (HR) = 0.52; 95% CI = 0.35–0.78; p = 0.001) analysis, as was TIA-1 expression (HR = 0.99; 95% CI = 0.94–0.99; p = 0.014). Tumors with high M3R expression were significantly more likely to be grade 2 compared to tumors with low M3R expression (85.7% vs. 67.1%, p = 0.002). The 5-year survival analysis showed a trend of a higher survival rate in patients with high M3R expression (46%) than patients with low M3R expression CRC (42%) (p = 0.073). In contrast to previous in vitro and animal model findings, this study demonstrates an increased survival for CRC patients with high M3R expression. This evidence is highly relevant for translation of basic research findings into clinically efficient treatments.

The Role of CPNE7 (Copine-7) in Colorectal Cancer Prognosis and Metastasis

“…While 3 of the 123 low-expression patients died and 10 survived, at 120 months, 127 high-expression patients died and 1 survived. The CPNE7 high/low expression patient group was classified as TNM stage 0, 1/2, 3 [15]. As a result of comparing the CPNE7 expression level and the survival rate of patients, it was confirmed that the higher the expression of CPNE7, the lower the survival rate of the patients, which was statistically significant.…”

Novel Therapeutic Approaches for Colorectal Cancer Treatment

“…Analyzing 754 surgical CRC tissue samples, Lobbes et al demonstrated that high expression of M3R correlated with enhanced survivability, particularly in cases with lower tumor grade and a non-mucinous subtype. This association was linked to a more favorable outcome compared to cases with low M3R expression, where survival significantly decreased and higher tumor grade and mucinous subtype were prevalent [32]. Genomic instability is a hallmark of CRC, and metastatic CRC (mCRC) characterized by deficient mismatch repair (dMMR) and MSI can effectively be treated using immune checkpoint inhibitors (ICI) such as pembrolizumab and nivolumab, approved by both the FDA and EMA [12,33,34].…”