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Review
. 2019 Apr 5:10:339.
doi: 10.3389/fphar.2019.00339. eCollection 2019.

The Endocannabinoid System as a _target in Cancer Diseases: Are We There Yet?

Estefanía Moreno  1   2 , Milena Cavic  3 , Ana Krivokuca  3 , Vicent Casadó  1   2 , Enric Canela  1   2
Affiliations
Review

The Endocannabinoid System as a _target in Cancer Diseases: Are We There Yet?

Estefanía Moreno et al. Front Pharmacol. .

Abstract

The endocannabinoid system (ECS) has been placed in the anti-cancer spotlight in the last decade. The immense data load published on its dual role in both tumorigenesis and inhibition of tumor growth and metastatic spread has transformed the cannabinoid receptors CB1 (CB1R) and CB2 (CB2R), and other members of the endocannabinoid-like system, into attractive new _targets for the treatment of various cancer subtypes. Although the clinical use of cannabinoids has been extensively documented in the palliative setting, clinical trials on their application as anti-cancer drugs are still ongoing. As drug repurposing is significantly faster and more economical than de novo introduction of a new drug into the clinic, there is hope that the existing pharmacokinetic and safety data on the ECS ligands will contribute to their successful translation into oncological healthcare. CB1R and CB2R are members of a large family of membrane proteins called G protein-coupled receptors (GPCR). GPCRs can form homodimers, heterodimers and higher order oligomers with other GPCRs or non-GPCRs. Currently, several CB1R and CB2R-containing heteromers have been reported and, in cancer cells, CB2R form heteromers with the G protein-coupled chemokine receptor CXCR4, the G protein-coupled receptor 55 (GPR55) and the tyrosine kinase receptor (TKR) human V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 (HER2). These protein complexes possess unique pharmacological and signaling properties, and their modulation might affect the antitumoral activity of the ECS. This review will explore the potential of the endocannabinoid network in the anti-cancer setting as well as the clinical and ethical pitfalls behind it, and will develop on the value of cannabinoid receptor heteromers as potential new _targets for anti-cancer therapies and as prognostic biomarkers.

Keywords: G protein-coupled receptor; cannabinoid CB1 receptor; cannabinoid CB2 receptor; endocannabinoids; ethical issues; marijuana legalization; receptor heteromer.

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Figures

FIGURE 1
FIGURE 1
A schematic representation of the main components of the endocannabinoid system (ECS). CBR – cannabinoid receptor, GPR – G protein-coupled receptor, PPAR – peroxisome-proliferator-activated receptors, FAAH – Fatty acid amide hydrolase, MAGL – Monoacylglycerol lipase, PLC – Phospholipase C, DAGL – Diacylglycerol lipase, ABHDx – Alpha beta hydrolase domain proteins, HSP – heat shock proteins, FLAT – FAAH-like anandamide transporter.
FIGURE 2
FIGURE 2
A schematic representation of CB2R-CXCR4, CB2R-GPR55 and CB2R-HER2 heteromers and their role as new _targets in cancer. In Panel (A), the activation of CB2R-CXCR4 heteromers inhibits prostate cancer cell migration and adhesion. The binding of CXCL12 to its receptor, CXCR4, induces CXCR4-mediated cell migration and adhesion. The application of both CXCR4 and CB2R agonists inhibits the effect of CXCR4 agonist, due to the presence of functional CB2R-CXCR4 heteromers. In Panel (B), the hypothetical effect of THC on the CB2R-GPR55 heteromer. At low concentrations, THC acts as a CB2R agonist promoting signaling. At higher concentrations, THC _targets GPR55, acting as an antagonist, and by cross-antagonism, inhibits CB2R signaling. In Panel (C), the proposed mechanism of control of the CB2R-HER2 heteromer in breast cancer is shown. The HER2-CB2R heteromer is disrupted by THC or by using a synthetic peptide with the amino acid sequence of specific transmembrane 5 domain (TM5) of the CB2R, triggering the inactivation of HER2 and producing antitumor responses.
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