Purinergic Calcium Signals in Tumor-Derived Endothelium.

Tumor microenvironment is particularly enriched with extracellular ATP (eATP), but conflicting evidence has been provided on its functional effects on tumor growth and vascular remodeling. We have previously shown that high eATP concentrations exert a strong anti-migratory, antiangiogenic and normalizing activity on human tumor-derived endothelial cells (TECs). Since both metabotropic and ionotropic purinergic receptors trigger cytosolic calcium increase ([Ca]c), the present work investigated the properties of [Ca]c events elicited by high eATP in TECs and their role in anti-migratory activity. In particular, the quantitative and kinetic properties of purinergic-induced Ca release from intracellular stores and Ca entry from extracellular medium were investigated. The main conclusions are: (1) stimulation of TECs with high eATP triggers [Ca]c signals which include Ca mobilization from intracellular stores (mainly ER) and Ca entry through the plasma membrane; (2) the long-lasting Ca influx phase requires both store-operated Ca entry (SOCE) and non-SOCE components; (3) SOCE is not significantly involved in the antimigratory effect of high ATP stimulation; (4) ER is the main source for intracellular Ca release by eATP: it is required for the constitutive migratory potential of TECs but is not the only determinant for the inhibitory effect of high eATP; (5) a complex interplay occurs among ER, mitochondria and lysosomes upon purinergic stimulation; (6) high eUTP is unable to inhibit TEC migration and evokes [Ca]c signals very similar to those described for eATP. The potential role played by store-independent Ca entry and Ca-independent events in the regulation of TEC migration by high purinergic stimula deserves future investigation.