Cannabinoid Signaling in Glioma Cells and Therapeutic implications

Gliomas are the most common primary brain tumors. Due to genetic and epigenetic alterations, malignant gliomas are highly resistant to radiation and chemotherapy. Mainstream therapeutic strategies for the management of these tumors are still mostly palliative, known to leave survivors with devastating neurological deficits, and frequently with a high risk of the disease recurrence. Significant alterations of a balance in the cannabinoid system between the levels of endogenous ligands and their receptors occur during malignant transformation in various types of cancer, including gliomas. Cannabinoids exert antiproliferative action in tumors. Induction of cell death by cannabinoid treatment relies on the generation of a proapoptotic sphingolipid ceramide, and disruption of signaling pathways crucial for regulation of cellular proliferation, differentiation, or apoptosis. Increased ceramide levels also lead to ER-stress and autophagy in drug-treated glioma cells. Beyond inhibition of tumor cell proliferation, cannabinoids impair tumor angiogenesis, invasiveness, and even gliomagenesis.