Cannabinoids receptor type 2, CB2, expression correlates with human colon cancer progression and predicts patient survival.

Esther Martínez-Martínez,Eva Tejerina,Paloma Martín,Irene Gómez,Antonio Sánchez,Laura Román,Jose M García,Antonio García Merino,Félix Bonilla,Antonio García De Herreros,Mariano Provencio

doi:10.18632/oncoscience.119

Abstract

Many studies have demonstrated that the endocannabinoid system (ECS) is altered in different tumor types, including colon cancer. However, little is known about the role of the ECS in tumor progression. Here we report the correlation between CB 2 expression and pathological data in a series of 175 colorectal cancer patients, as well as the response of the HT29 colon cancer-derived cell line upon CB 2 activation. CB 2 mRNA was detected in 28.6% of samples tested. It was more frequent in N+ patients and predicts disease free survival and overall survival in colon cancer. In positive samples, CB 2 was expressed with great intensity in tumor epithelial cells and correlated with tumor growth. Treatment of HT29 with CB 2 agonist revealed membrane loss of E-cadherin and SNAIL1 overexpression. A direct correlation between CB 2 and SNAIL1 expression was also found in human tumors. CB 2 receptor expression is a poor prognostic marker for colon cancer and the activation of this receptor, with non-apoptotic doses of agonists, could be collaborating with disease progression. These results raise the question whether the activation of CB 2 should be considered as anti-tumoral therapy.

Highlights

Colorectal cancer (CRC) is the third most common malignancy and the fourth cause of cancer mortality worldwide
Adaptive changes in the endocannabinoid system (ECS) have been observed in intestinal biopsies from colon cancer patients, such as increased endocannabinoid levels, down-regulation of
In this study we verified that Cannabinoid receptor type 2 (CB2) is up-regulated in epithelial cells from tumor tissues compared with their normal counterparts

Summary

INTRODUCTION

Colorectal cancer (CRC) is the third most common malignancy and the fourth cause of cancer mortality worldwide. It is unlikely that inflammation initiates sporadic CRC, chronic inflammation follows tumor development, throughout the progression of the disease a considerable proportion of patients display robust inflammatory infiltration and increased expression of pro-inflammatory cytokines [1]. Several authors have suggested that cannabinoid agonists have anti-tumoral actions based on in vitro studies and with animal models. Some studies have found that endocannabinoids and cannabinoid receptor levels are higher in malignant cells or tissues than in non-malignant ones and that there are cases where increased ECS activity correlates with some markers of tumor aggressiveness [14,15,16,17,18]. We analyzed, in a large series of colorectal cancer patients, the expression of the CB2 receptor and its relation with the progression of the disease, in order to shed light on this issue

RESULTS

DISCUSSION

METHODS