Papel del receptor huérfano GPR55 en la fisiopatología del cáncerimplicación en la proliferación e invasión de células tumorales

Abstract

GPR55 is an orphan G protein-coupled receptor that has been proposed to be engaged by lysophospholipids and cannabinoids. Though little is known about the physiological function of GPR55, emerging evidences point to important regulatory functions throughout the body. In this Thesis we studied the role of GPR55 in cancer physio-pathology. We found that GPR55 is expressed in human tumors from different origins, and that this expression is higher in the transformed tissues as compared with the corresponding non-transformed tissues and correlates with tumor aggressiveness. Our results show that GPR55 expression confers a series of adaptative advantages on cancer cells that make them more aggressive. First, we demonstrate that GPR55 drives cancer cell proliferation, through activation of the ERK/MAPK cascade, both in cell cultures and in vivo, which results in the promotion of tumor growth in xenograft-based and chemical-carcinogenesis animal models of cancer. Second, we show that GPR55 expression favors another set of capabilities that are intimately related to tumor progression in general and the generation of metastasis in particular. Thus, GPR55 promotes anchorage-independent growth, migration and invasion of cancer cells in culture through activation of Gq proteins and the generation of lung metastasis in vivo. Finally, we investigated if GPR55 is involved in the biphasic effect of cannabinoids on cancer cell proliferation (low concentrations producing pro-proliferative responses while high concentrations inducing anti-proliferative effects). Our data show that GPR55 modulates the proliferation-inducing response produced by low concentrations of cannabinoids, and suggest that this action may be produced by functional interaction of GPR55 with the classical cannabinoid receptor CB1. Together, our data suggests that GPR55 could be a new biomarker with prognostic value and a therapeutic target in oncology.