During inflammatory processes and cancer, ATP and other nucleotides accumulate in tissue microenvironment to reach concentrations much higher than those measured in healthy tissues. In tumors, extracellular ATP origins from necrotic and inflammatory cells, but it can also be directly released from cancer cells. There is increasing interest in the therapeutic potential of purinergic signaling for the treatment of cancer. The functional significance of purinergic signaling has been investigated on cancer cells but not on tumor endothelium. P2 receptors are highly expressed by virtually all tumors and positive or negative modulation of P2 subtypes promotes cancer cell death or growth inhibition. In particular, altered P2X7R expression and function could play a role in tumor progression. However, whether P2X7R exerts a promoting or suppressive tumor’s growth is still a controversial issue and its underlying mechanism remains unknown.

            Recently, we suggested that strong purinergic stimulation inhibits tumor-derived EC migration and enhances pericyte attraction, potentially leading to vessel normalization. These events are mediated by the interplay between calcium and cAMP signaling mainly triggered by P2X7 and P2Y11 receptors. 

This work provides a novel mechanistic insight and unveils a new and potentially attractive role for purinergic signalling as stabilizing and normalizing agent for tumor vasculature, which could be used to develop novel anti-angiogenic therapeutic strategies.