la segnalazione purinergica inibisce la migrazione delle cellule endoteliali tumorali: meccanismi e implicazioni funzionali

Neo-vascularization is required for tumour growth and expansion. Endothelial cells play a major role in tumoral vessel formation (angiogenesis) and thus tumor-derived endothelial cells are good models to study this process. Extracellular adenosin trisphosphate (ATP) is a potent mediator of endothelium-dependent relaxation in various species; it also induces intracellular calcium ([Ca2+]i) signals in ECs, that could play a significant role in tumor progression stages, including angiogenesis. ATP binds purinergic receptors involved in inflammation. In particular, P2R family has been widely connected to tumor neo-angiogenesis. In this work we investigated the involvement of ATP in normal and pathological angiogenesis, using human microvascular endothelial cells (HMVEC) and breast tumor-derived endothelial cells (BTECs) as models. High pathological ATP concentration (100 μM) inhibits BTECs migration and tubulogenesis, while it was unaffective on HMVECs. The same ATP concentration triggers Ca2+ signals in BTEC distinguishable from those activated in HMVECs. Moreover, 100 μM ATP promotes actin remodelling and spreading in BTECs: on the other hand, it drastically reduces permeability in the same cells. BzATP (P2X7/P2Y11 agonist) partially mimicks the effects of ATP, whereas BBG (P2X7 antagonist) and shP2X7 transfection (shRNA1-2) partial restore the inibitory effects of ATP. Further investigations lead us to suggest a role of cAMP/Epac1 pathway in this process. Taken together, our results show that ATP is involved in the regulation of tumor angiogenesis in vitro, mainly acting through P2X7R and P2Y11R activation.