| The effect of endocannabinoid receptors on receptiveness of the endometrium and the role of endocannabinoids in metastatic niche creation

Reuven Reich, Ph.D.

The effect of endocannabinoid receptors on receptiveness of the endometrium

Plasma AEA levels fluctuate with the natural menstrual cycle, with the highest levels during the follicular phase. Likewise, the expression and distribution of FAAH, NAPE-PLD, CB1 and CB2 in female reproductive tissues also vary with the menstrual cycle suggesting that the eCS expression is under hormonal control.

Implantation is the very early stage of pregnancy at which the blastocyst adheres and invades the wall of the uterus. The process of implantation implies a highly synchronized and complex bidirectional communication between the conceptus and the luminal endometrial cells, and it could be divided in three stages: apposition, adhesion and penetration.

The endocannabinoid system plays an important role during the process of implantation. Studies in mice have shown that a delicate balance between anandamide (AEA) synthesis (driven mainly by NAPE-PLD) and degradation (mainly by FAAH) is necessary to ensure an appropriate ‘AEA tone’ during implantation.

In our studies, we examine the role of the endocannabinoid receptors in patients with repeated implantation failure (RIF).


Are endocannabinoids involved in the creation of metastatic niche?

 Endocannabinoids are produced in several peripheral tissues resulting in cell-type and location-specific profiles so that the eCB pattern in the tumor microenvironment depends on the tumor’s origin and site of primary growth and metastasis. Tumor growth is associated with an increase of 2-arachidonoylglycerol (2-AG) both at the site of the primary tumor and in plasma of the patients. It steadily increased over the course of cancer development and metastasis, suggesting that the growing tumor and circulating metastatic tumor cells secrete large amounts of 2-AG, sufficient enough to manifest in high plasma concentrations.

It is likely that the tumor itself mainly secretes 2-AG. The endocannabinoids have diverse effects on cannabinoid receptors including the typical cannabinoid receptor 1 and 2 (CB1, CB2) and other non typical ones.

Treatment with exo- and endogenous cannabinoids reduced cancer growth in several rodent models and cell culture experiments, but CB2 expression of the tumor itself has been recently associated with poor prognosis in breast cancer.

In our studies we examine the effect of the endocannabinoid system on the early stages of metastatic spread, the formation of the metastatic niche.


Key words: ovarian cancer , exosomes, ncRNAs, tumor progression