Fig. 3

ATP’s roles in intravasation, circulation, extravasation and colonization. a Extracellular ATP’s role in overcoming anoikis. ATP induces the late G1 gene cyclin A expression and stimulates anchorage-independent cell growth by activating P2Y receptors. P2XR can also activate the stimulation of intracellular pathways, such as the PI3K/AKT pathways, that contribute to overcoming anoikis resistance. b Extracellular ATP plays a crucial role in platelet-mediated transmigration of tumor cells through the vascular endothelium. In the bloodstream, cancer cells rapidly associate with and are coated by the circulating platelets. This process triggers ATP release from platelets and facilitates tumor cell passage across the endothelial layer. More specifically, the ATP released from active platelet-activation of the P2Y2 receptor induces the endothelial cells to retract from each other, which promotes the opening of the endothelial barrier, thus facilitating cancer cell intravasation and extravasation. c During extravasation, extracellular ATP activates the P2Y1 receptor of vascular endothelial cells, and induces the releases of VEGF2 to initiate angiogenesis in the metastatic niche. Extracellular ATP acts on P2X7 receptors of immune cells to stimulate the release of plasma membrane-derived microvesicles and exosomes. These vesicles may potentially impact the formation of the pre-metastatic niche and lead to an increased capacity for metastatic outgrowth