Endocannabinoid signaling in glioma

Abstract

High-grade gliomas constitute the most frequent and aggressive form of primary brain cancer in adults. These tumors express cannabinoid CB 1 and CB 2 receptors, as well as other elements of the endocannabinoid system. Accruing preclinical evidence supports that pharmacological activation of cannabinoid receptors located on glioma cells exerts overt anti-tumoral effects by modulating key intracellular signaling pathways. The mechanism of this cannabinoid receptor-evoked anti-tumoral activity in experimental models of glioma is intricate and may involve an inhibition not only of cancer cell survival/proliferation, but also of invasiveness, angiogenesis, and the stem cell-like properties of cancer cells, thereby affecting the complex tumor microenvironment. However, the precise biological role of the endocannabinoid system in the generation and progression of glioma seems very context-dependent and remains largely unknown. Increasing our basic knowledge on how (endo)cannabinoids act on glioma cells could help to optimize experimental cannabinoid-based anti-tumoral therapies, as well as the preliminary clinical testing that is currently underway.

The Cytotoxic Effects of Cannabidiol and Cannabigerol on Glioblastoma Stem Cells May Mostly Involve GPR55 and TRPV1 Signalling

“…Taken together, we speculate that both CBD and CBG may induce cell differentiation due to their relatively stronger effects on GSCs via GPR55 signalling suppression that also suppresses GSCs stemness genes. This hypothesis must be further confirmed; however, it corroborates all previous studies on cannabinoids and CNR ligands that demonstrated GSC differentiation [ 12 , 13 , 14 ]; however, these studies did not mention the potential role of GPR55 ( Scheme 1 ).…”

“…Kolbe et al [ 24 ] also reported highly variable expressions of CB1 and CB2 in primary GBM cells, observing low CNR2 gene expression but not always low CB2 protein expression. Over-expressed levels of specific CNRs are expected in all cancer cells [ 39 ] due to the well-documented high anticancer activity of the endogenous endocannabinoid system in the brain [ 13 , 40 ], which undoubtedly plays a role in glioma malignancy. For example, in GBMs expressing high CB1 level, CBD counteracted tumour growth also by inhibiting the endocannabinoid anandamide-degrading enzyme, thereby enhancing endocannabinoid activity.…”

“…As reviewed by Alves et al [ 11 ], adjuvant treatments with natural products, e.g., cannabinoids, can decrease GSC viability and thus show promise for eliminating GSCs and preventing tumour recurrence. Based on current knowledge, cannabinoids and synthetic ligands of their receptors target GSCs and their stemness-related signalling pathways, forcing them to differentiate [ 12 , 13 , 14 ].…”

“…CBG more than CBD binds and dilates transmembrane TRPV1 Ca 2+ permeable pores and thus more or less desensitizes TRPV1 and perturbs its signalling activity [ 27 ] in high grade astrocytoma [ 30 ] and NSCs [ 31 ]. Yet CBG and CBG’s differential binding affinity to the three receptors affect their specific signalling in GBM and GSC cells [ 13 , 32 , 33 ].…”

The Synthetic Cannabinoid URB447 Exerts Antitumor and Antimetastatic Effect in Melanoma and Colon Cancer

“…It is the omnipresence what makes CB receptors a potential target for several pathologies [ 5 , 6 ]. In fact, CB receptors are expressed in a wide variety of cancers with different origin, such as glioma and melanoma, to name a few [ 7 , 8 ]. However, the role of these receptors is not yet very well understood.…”