Modulation of purinergic signaling in endothelial cells by tumor microenvironment.

ABSTRACT

Purinergic signaling plays a crucial role in vascular endothelium functions. In particular, ionotropic P2X receptors (P2XRs) are engaged in various intracellular pathways through which endothelial cells (ECs) adapt to external stimuli. However, very little is known about the impact of P2XRs on vascular remodeling during carcinogenesis. We previously demonstrated that high purinergic stimulation impairs the migratory phenotype of tumor-derived endothelial cells (TECs) but not of normal ECs. Since P2XRs are sensitive to different physical and chemical factors, we investigated the impact of tumor microenvironment (TME) on healthy ECs to verify the ability of cancer cells to affect endothelial migratory phenotype through purinergic signaling tuning. More specifically, we focused on P2XR modulation by two different types of TME, mimicking breast and pancreas cancer milieux, which show very different features in terms of vascularization and composition. ECs conditioning with both cancer cell types induced a significant upregulation of some of the most represented P2XR. However, only conditioning with MCF-7 cells and not that with PANC-1 cells was able to alter the migratory phenotype of normal ECs supporting a P2XR-mediated inhibition of cell migration. The differences observed between the two cancer cells could be due to their different proliferative potential and the subsequent different extracellular pH. In addition, in agreement with some of our previous data, the P2XR-induced inhibition of EC migration seems to be independent of calcium signals, as conditioned ECs didn't reveal any changes in the long-lasting responses evoked by purinergic agonists. Collectively, highlighting a significant P2RX modulation by TME, our data strengthen the hypothesis that purinergic signaling may play a central role in vascular remodeling during carcinogenesis. However, the molecular routes upstream and downstream of this modulation remain to be elucidated.