GPR55 and LPI: an inflammatory-oncogenic axis in the colon

Lipids are molecules with a central role in energy metabolism; however, they also function as signal transmitters. Among these lipids, several new species have been recently discovered that are able to transmit information to cancer cells in the large intestine. In the past years, the presence of so-called endocannabinoids have been described to in the mammalian organism. They transmit signals via their respective receptors located on cancer cells. In this respect they are similar to certain components of the Cannabis plant (hence their name). These lipids and their responsive receptors build an axis that is thought to influence the development of inflammation and cancer. In our project, we intend to investigate such a ligand-receptor axis that consists of the atypical cannabinoid receptor GPR55 and its endogenous ligand lysophosphatidylinositol (LPI). GPR55 behaves differently from the known cannabinoid receptors with respect to its intracellular signaling pathways. Although being activated by endocannabinoids, its main ligand has been identified as a phospholipid, namely LPI. Since GPR55 is highly present in the human large intestine, we will investigate whether the GPR55/LPI axis drives disease progress in inflammatory bowel diseases (IBD) and whether it promotes the growth of colon carcinoma. To this end, GPR55 expression will be measured in tumor tissue and biopsies from colonic mucosa with adequate protein assays and histological methods. LPI is measured by mass spectrometry in serum taken from IBD and colon carcinoma patients. The role of GPR55 in these diseases has not yet been investigated and it is still unclear as to whether this receptor may be a valuable pharmacological target for treatment. The proposal therefore combines the investigation of the inflammatory and cancerogenous properties of a ligand-receptor axis and its therapeutic exploitation together with its usefulness as a biomarker of disease. The project will create the necessary basis to answer the question whether pharmacological manipulation of the GPR55 receptor/LPI ligand axis could represent a possible option in the pharmacotherapy of inflammation and cancer of the large intestine.

The Endocannabinoid system: a critical player in inflammatory bowel disease and colon cancer Many lipid molecules act as ligands on cancer cells. Some of these bioactive lipids belong to the family of endocannabinoids or endocannabinoid-like lipids and they critically influence many functions of cancer cells. Endocannabinoids are produced by the organism and act in a similar way as THC from Cannabis. Some of these endocannabinoids/endocannabinoid-like lipids have been intensively investigated in recent years. From preclinical experiments we know that endocannabinoids and cannabinoid receptors, which are part of the endocannabinoid system, fulfill a protective role in intestinal inflammation and colon cancer. However, the role of the endocannabinoid system in inflammatory bowel disease (IBD) and colon cancer has hardly been investigated in humans. Our project, therefore, intended to focus on the role of this system in human gastrointestinal disease in order to provide a basis for potential cannabinoid-based therapy.Many endocannabinoids/endocannabinoid-like lipids were elevated in plasma from patients with IBD and colorectal cancer suggesting an involvement in these diseases. In contrast, the amount of cannabinoid receptors (in particular of cannabinoid receptor 1) was decreased in patients with IBD indicating that the loss of the receptor may diminish the protection against inflammation. The presence of the cannabinoid receptor 1 was also reduced in tumor tissue of colon ancer patients when compared to tumor-free tissue. As a possible reason for this reduced presence we found out that the receptor was epigenetically suppressed and therefore probably not able to fulfill its protective role in colon cancer. In contrast, the presence of GPR55, a cannabinoid-responding protumorigenic receptor was not diminished in tumors from colon cancer patients because it was not epigenetically suppressed. These results suggested that there may have been a shift in the presence of tumor-rejecting to tumor-promoting cannabinoid-sensitive receptors in colon cancer. In addition, the lipid molecule activating the GPR55 receptor was strongly increased in plasma of colon cancer patients. Collectively, we could show in our project that the components of the endocannabinoid system were differenty expressed in IBD patients and healthy controls. Cannabinoid and GPR55 receptors play an important role also in colon cancer in humans. The inflammation- and tumor-suppressing role of the cannabinoid receptor 1 seems to be hampered in IBD and colon cancer. With our data, we hope that we have substantially contributed to a basis for a modern cannabinoid-based therapy.