GPR55 in tumorigenesis and metastasis of colon cancer

G protein coupled receptors (GPCRs) promote tumor growth and metastasis and thus represent important targets for antitumor treatment. The putative cannabinoid receptor G protein-coupled receptor 55 (GPR55) has recently emerged as a potential novel target because of its involvement in several hallmarks of cancer, such as proliferation, invasion and angiogenesis. The bioactive lipid lysophosphatidylinositol (LPI) was previously characterized as the endogenous ligand of GPR55 and found elevated in ovarian cancer suggesting a potential role of the LPI/GPR55 axis in tumor development. The presence of GPR55 in epithelia of the gastrointestinal tract (GI) suggests a role for GPR55 also in GI tumorigenesis. In the current project proposal, we therefore want to explore the unknown role of GPR55 in tumor growth and metastasis of colon cancer and hypothesize that GPR55 contributes to growth and metastasis of colon cancer. GPR55 will be investigated in the colon cancer cell lines HCT116 and SW480 by in vitro assays of proliferation, apoptosis, migration and invasion and in LPI-related signaling pathways. In a model of colitis- associated colorectal cancer in wild type and GPR55-/- knockout mice, the pathological importance of GPR55 during tumorigenesis is explored in vivo. There, we will investigate whether GPR55 is involved in proliferation of malignant cells and in the expression of oncogenic transcription factors, such as STAT3 and NF-kappa B. In an in vivo model of metastasis, we will explore if GPR55 contributes to the spread of colon cancer cells into secondary organs. The importance of GPR55 and LPI in carcinogenesis will be finally examined in samples of human colon carcinoma tissue and serum from colon carcinoma patients. The results from this project should provide important information as to whether pharmacological manipulation of GPR55 may be a valuable therapeutic approach for colon and maybe other cancers and whether LPI could be a useful biomarker for colon cancer.

In our project, we investigated the role of the GPR55 receptor in the development and metastasis of colon carcinoma. GPR55 is a lipid sensing receptor that is able to respond to cannabinoids, and it is widely distributed in the gastrointestinal tract. Cannabinoid receptors and GPR55 are part of the endocannabinoid system, a physiological entity that controls homeostasis in many organs of the body. The receptors are thought to interact with each other in the homeostatic control. Fundamental physiologic mechanisms, such as appetite, energy expenditure, emotions, but also pathophysiologic mechanisms of inflammation, pain, depression and cancer are influenced by the endocannabinoid system. GPR55, unlike cannabinoid receptors, increases tumor burden in the colon. While cannabinoid receptors play a protective role in gastrointestinal diseases, GPR55 seems to exert opposing effects, in particular to cannabinoid receptor 1 (CB1), indicating complex regulatory mechanisms within the endocannabinoid system. For the first time we could show that these receptors oppose each other in pathophysiological situations. We, thus, established that GPR55 promotes intestinal inflammation while CB1 is protective. The GPR55 receptor also promotes migration of colon cancer cells when treated with its endogenous ligand, a phospholipid from the cell membrane. We found that the compound is elevated in the blood of colon cancer patients in comparison to healthy individuals. GPR55 promotes adhesion of colon cancer cells onto endothelial cells indicating that it may play a role of dissemination of cancer cells to different organs. When blocking the receptor, we noticed that inflitration of colon cancer cells into liver tissue was stronly reduced. Most importantly, GPR55 is involved in the regulation of leukocytes within the tumor microenvironment of colonic tumors in a way that supports tumor growth. The absence of the receptor in tumor tissue seems to favor a leukocyte population that slows down the growth of colonic tumors. In patients with colorectal cancer, high expression of GPR55 was significantly associated with reduced relapse-free survival highlighting the human relevance of our findings. Pharmacological manipulation of GPR55 may be a valuable therapeutic approach for colon and maybe other cancers. Additionally, its endogenous ligand could be a useful biomarker for colon cancer.