The putative cannabinoid receptor GPR55 has been shown to play a tumor-promoting role in various cancers, and is involved in many physiological and pathological processes of the gastrointestinal (GI) tract. While the cannabinoid receptor 1 (CB 1 ) has been reported to suppress intestinal tumor growth, the role of GPR55 in the development of GI cancers is unclear. We, therefore, aimed at elucidating the role of GPR55 in colorectal cancer (CRC), the third most common cancer worldwide. Using azoxymethane (AOM)-and dextran sulfate sodium (DSS)-driven CRC mouse models, we found that GPR55 plays a tumor-promoting role that involves alterations of leukocyte populations, i.e. myeloid-derived suppressor cells and T lymphocytes, within the tumor tissues. Concomitantly, expression levels of COX-2 and STAT3 were reduced in tumor tissue of GPR55 knockout mice, indicating reduced presence of tumor-promoting factors. By employing the experimental CRC models to CB 1 knockout and CB 1 /GPR55 double knockout mice, we can further show that GPR55 plays an opposing role to CB 1 . We report that GPR55 and CB 1 mRNA expression are differentially regulated in the experimental models and in a cohort of 86 CRC patients. Epigenetic methylation of CNR1 and GPR55 was also differentially regulated in human CRC tissue compared to control samples. Collectively, our data suggest that GPR55 and CB 1 play differential roles in colon carcinogenesis where the former seems to act as oncogene and the latter as tumor suppressor.

Preclinical studies have demonstrated that the endocannabinoid system (ECS) plays an important role in the protection against intestinal inflammation and colorectal cancer (CRC); however, human data are scarce. We determined members of the ECS and related components of the ‘endocannabinoidome’ in patients with inflammatory bowel disease (IBD) and CRC, and compared them to control subjects. Anandamide (AEA) and oleoylethanolamide (OEA) were increased in plasma of ulcerative colitis (UC) and Crohn’s disease (CD) patients while 2-arachidonoylglycerol (2-AG) was elevated in patients with CD, but not UC. 2-AG, but not AEA, PEA and OEA, was elevated in CRC patients. Lysophosphatidylinositol (LPI) 18:0 showed higher levels in patients with IBD than in control subjects whereas LPI 20:4 was elevated in both CRC and IBD. Gene expression in intestinal mucosal biopsies revealed different profiles in CD and UC. CD, but not UC patients, showed increased gene expression for the 2-AG synthesizing enzyme diacylglycerol lipase alpha. Transcripts of CNR1 and GPR119 were predominantly decreased in CD. Our data show altered plasma levels of endocannabinoids and endocannabinoid-like lipids in IBD and CRC and distinct transcript profiles in UC and CD. We also report alterations for less known components in intestinal inflammation, such as GPR119, OEA and LPI.

Systemic inflammation leads to increased expression of spinal cyclooxygenase (COX)‐2 and to a subsequent increase of prostaglandin (PG) biosynthesis, which contribute to the development of hyperalgesia and allodynia. In this study, endotoxin caused a sequential induction of membrane bound prostaglandin E synthase‐1 and lipocalin‐type PGD synthase (L‐PGDS) in the mouse spinal cord. L‐PGDS expression was detected in the leptomeninges, oligodendrocytes, and interestingly, in discrete perivascular cells. Endotoxin‐caused increase was most prominent in oligodendrocytes. Endotoxin‐induced COX‐2 and membrane bound prostaglandin E synthase‐1 were restricted to the leptomeninges and perivascular cells. COX‐1 was not influenced by endotoxin. We found COX‐1 expressed in microglia, some of them in close proximity to L‐PGDS‐positive oligodendrocytes and co‐localization of COX‐1 with L‐PGDS in perivascular and leptomeningeal cells under control conditions. It can be assumed, that PGD2 biosynthesis under control conditions is mediated via COX‐1 and that during inflammation, increased PGD2 is dependent on COX‐2. We found the PGD2 receptors DP1 and chemoattractant receptor homologous molecule expressed on T helper type 2 cells (CRTH2) localized in neurons of the dorsal, and motoneurons in the ventral horn. The localization of the PGD2 receptors DP1 and CRTH in spinal cord neurons, particularly in neurons of lamina I and II involved in the processing of nociceptive stimuli, supports a role of PGD2 under inflammatory conditions.

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