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WIREs Membr Transp Signal

Targeting endocannabinoid signaling in tumor‐associated macrophages as treatment for glioblastoma multiforme

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Glioblastoma multiforme (GBM) is the most common form of primary brain tumor and is diagnosed in approximately 15,000 people each year in the United States alone. No cure for this type of cancer exists, and the current standard of care treatments provide little benefit and are associated with debilitating side effects. Recent evidence shows that a large number of tumor‐associated macrophages (TAMs) invade the GBM tumor mass and secrete factors that directly and indirectly promote tumor growth. TAMs express a panel of unique receptors that could be targeted for therapeutic benefit. One such receptor, cannabinoid receptor 2 (CB2), is a member of the endocannabinoid (eCB) signaling system, and its activation has been shown to tightly control the migration and phenotype of both macrophages and microglia. Additional receptors, also engaged by eCBs and cannabinoid‐like compounds, are expressed by macrophages and microglia. These receptors also control cell migration and phenotype, but exhibit distinct pharmacological profiles and operate through a different mechanism of action. Strong evidence accumulated over the past decade indicates that membrane receptors expressed by TAMs represent novel targeting opportunities to treat GBM tumor progression. Here we review studies that significantly increased our understanding of the molecular mechanism of action of receptors engaged by eCBs and cannabinoid‐like compounds expressed by GBM tumor cells and TAMs. This evidence provides a strong rationale for developing new therapeutics that target the eCB signaling of TAMs for the treatment of GBM while minimizing the typical side effects associated with standard care. WIREs Membr Transp Signal 2014,3:39–51. doi: 10.1002/wmts.101

Conflict of interest: The authors have declared no conflicts of interest for this article.

Cannabinoid (CB) receptors expressed in the glioblastoma multiforme (GBM) tumor mass. Schematic of the composition of various cell types forming GBM tumors show that CB receptors can be targeted for the treatment of this disease. CB1 and CB2 receptors are expressed by microglia, GBM cells, GBM stem cells, and endothelial cells, and can be targeted to promote cell death in GBM and control inflammation by modulating the phenotype of microglia. New CB receptors may also be selectively targeted to promote these activities. Functions relevant for each cell type in GBM are outlined in text boxes. Arrows designate key signaling factors for GBM growth and survival.
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