Review
The endocannabinoid signaling system in cancer

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Changes in lipid metabolism are intimately related to cancer. Several classes of bioactive lipids play roles in the regulation of signaling pathways involved in neoplastic transformation and tumor growth and progression. The endocannabinoid system, comprising lipid-derived endocannabinoids, their G-protein-coupled receptors (GPCRs), and the enzymes for their metabolism, is emerging as a promising therapeutic target in cancer. This report highlights the main signaling pathways for the antitumor effects of the endocannabinoid system in cancer and its basic role in cancer pathogenesis, and discusses the alternative view of cannabinoid receptors as tumor promoters. We focus on new players in the antitumor action of the endocannabinoid system and on emerging crosstalk among cannabinoid receptors and other membrane or nuclear receptors involved in cancer. We also discuss the enzyme MAGL, a key player in endocannabinoid metabolism that was recently recognized as a marker of tumor lipogenic phenotype.

Section snippets

Importance of lipid mediators in cancer

The reprogramming of energy metabolism that occurs in tumor cells can be rightfully included among the hallmarks of cancer [1]. Besides switching from oxidative to glycolytic metabolism, tumor cells require anabolic processes to augment the synthesis of proteins, nucleic acids, and lipids. Whereas most tissues besides the liver, adipose tissue, and breast acquire fatty acids primarily from dietary sources, tumor cells increase de novo fatty acid synthesis to produce membrane building blocks

Brief introduction of the ECS

A significant number of studies have been performed to clarify the biological role of the ECS, its regulatory functions in health and disease, and the potential of its pharmacological exploitation. The ECS comprises (i) two GPCRs, CB1 and CB2; (ii) their endogenous ligands, the endocannabinoids, which are lipid molecules containing long-chain polyunsaturated fatty acids, amides, esters, and ethers [e.g., anandamide and 2-arachidonoylglycerol (2-AG)]; and (iii) the enzymes that regulate

Overview of the antitumor effects of drugs targeting the ECS

Antitumor properties of cannabis compounds were originally proposed more than 35 years ago, but the potential of targeting the ECS in cancer has recently attracted increasing interest. Accumulating evidence from preclinical studies and clinical use of cannabinoid-based drugs for inhibition of chemotherapy-induced nausea, vomiting, and cancer-associated pain has revealed an intimate relationship between the ECS and cancer 8, 9, 10. Natural and synthetic (endo)cannabinoids inhibit cell

Crosstalk among CB receptors and other receptors and involvement of lipid rafts

CB receptors are colocalized and can integrate their signal transduction pathways with a large variety of other receptors. There is crosstalk between CB receptors and TKRs 29, 40, 45, 46, 47, chemokine receptors [48], and nuclear receptors such as estrogen receptors (ERs) and PPAR-γ 49, 50, 51, 52. This blocks their downstream signaling, which results in impaired cell proliferation, reduction of the invasive phenotype, and inhibition of angiogenesis. (Endo)cannabinoid administration induced

ECS role in the physiopathology of cancer: is it really contradictory?

As summarized above, the antitumor action of drugs targeting the ECS affects almost all of the recognized hallmarks of cancer, making (endo)cannabinoids attractive tools for treating cancer [1]. However, beyond the pharmacology of exogenous (endo)cannabinoids and endocannabinoid-related drugs, we have to take into account that the ECS is ubiquitously expressed in cells and therefore endocannabinoids are naturally produced within cells in response to different stimuli. Thus, the antitumor

ECS and MAGL: lipogenic phenotype of cancer

Tumor cells adapt their metabolism towards a lipogenic phenotype, which correlates with high expression of MAGL, a key element in the fatty acid network. MAGL is a 33-kDa serine hydrolase belonging to the superfamily of α- and β-hydrolases with a GXSXG motif [88]. It was initially known for its role in lipolysis, specifically in hydrolysis of monoacylglycerols from stored triacylglycerols to generate free fatty acids and glycerol. This is a fundamental process for generating energy during

Concluding remarks

The literature strongly suggests a role for the ECS in the pathogenesis of cancer and great therapeutic promise of its pharmacological exploitation. It is evident that both endogenous and (endo)cannabinoid-like molecules, acting through cannabinoid receptor-dependent and -independent mechanisms, target key signaling pathways affecting all the hallmarks of cancer. Moreover, the ECS is one of the lipid signaling pathways that could be altered when tumors switch to a lipogenic phenotype, as

Acknowledgments

This work was supported by Associazione Educazione e Ricerca Medica Salernitana (ERMES) and by Associazione Italiana per la Ricerca sul Cancro (AIRC-IG 13312).

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