Down-Regulation of Cannabinoid Type 1 (CB1) Receptor and its Downstream Signaling Pathways in Metastatic Colorectal Cancer

Abstract

Changes in the regulation of endocannabinoid production, together with an altered expression of their receptors are hallmarks of cancer, including colorectal cancer (CRC). Although several studies have been conducted to understand the biological role of the CB1 receptor in cancer, little is known about its involvement in the metastatic process of CRC. The aim of this study was to investigate the possible link between CB1 receptor expression and the presence of metastasis in patients with CRC, investigating the main signaling pathways elicited downstream of CB1 receptor in colon cancer. Fifty-nine consecutive patients, with histologically proven colorectal cancer, were enrolled in the study, of which 30 patients with synchronous metastasis, at first diagnosis and 29 without metastasis. A low expression of CB1 receptor were detected in primary tumor tissue of CRC patients with metastasis and consequently, we observed an alteration of CB1 receptor downstream signaling. These signaling routes were also altered in intestinal normal mucosa, suggesting that, normal mucosa surrounding the tumor provides a realistic picture of the molecules involved in tissue malignant transformation. These observations contribute to the idea that drugs able to induce CB1 receptor expression can be helpful in order to set new anticancer therapeutic strategies.

Cannabinoids in the landscape of cancer

“…It is therefore no surprise that there remains ambiguity in its precise role within cancer pathophysiology (Wu 2019 ). Many pre-clinical studies and histological analysis of patient tumours, suggest that an upregulation in the CB 1 and CB 2 receptors, endogenous ligands and over-activation of the ECS correlates with more aggressive tumours (Dariš et al 2019 ) although other reports have concluded the contrary (Jung et al 2013 ; Tutino et al 2019 ). Cancer is a heterogenous disease and current evidence should be interpreted on the basis that different tumour types have been shown to exhibit various levels of CB receptors as well as ECS components.…”

The Endocannabinoid System: A Target for Cancer Treatment

“…In other studies, CB1 up-regulation was associated with a shorter survival time of CRC patients with stage II microsatellite-stable [32] or stage IV tumors [38]; whereas, CB2 receptor up-regulation in CRC tissue was correlated to higher proliferation levels and lymph node involvement, suggesting that also its expression could be a negative prognostic factor [34]. Conversely, in hepatocarcinoma high levels of both receptors have been associated with better disease-free survival rates [39,40]. Despite the reported evidence, the altered expression of CB receptors in several GI cancers is not strictly related to a straightforward cause and effect and must be further investigated.…”

The Interplay between Cancer Biology and the Endocannabinoid System—Significance for Cancer Risk, Prognosis and Response to Treatment

“…The expression of CB2R is a poor prognostic factor in CRC and its activation via the AKT/GSK3β signalling pathway has been linked with a more aggressive phenotype [62]. On the other side, the down-regulation of CB1R has been linked with metastatic CRC [63]. Endogenous and synthetic cannabinoids elicit the suppression of CRC cells proliferation and migration and stimulate apoptosis, via receptor-dependent and independent mechanisms [64].…”