Secretion of adenine nucleotides by platelets induces cancer cell extravasation and metastasis.
Major finding: Secretion of adenine nucleotides by platelets induces cancer cell extravasation and metastasis.
Mechanism: ATP-mediated stimulation of P2Y2 receptors enables tumor cell migration across the endothelium.
Impact: Inhibition of P2Y2 receptors may impair metastasis without affecting normal platelet function.
Tumor-activated platelets promote cancer cell survival and metastasis, and inhibition of platelets with low-dose aspirin is associated with decreased risk of metastasis. Secretion of growth factors and other small molecules from platelets has been suggested to contribute to tumor cell dissemination, but the mechanisms by which platelets facilitate metastatic spread remain unclear. Schumacher and colleagues found that the presence of tumor-activated platelets but not unactivated platelets enhanced cancer cell transmigration across a layer of endothelial cells and triggered a loss of interendothelial cell junctions. This prometastatic effect was dependent on secretion of adenine nucleotides such as ATP and ADP from platelet dense granules; addition of ATP stimulated tumor cell transendothelial migration, whereas degradation of adenine nucleotides blocked the platelet-induced increase in endothelial permeability and tumor cell transmigration. Inhibition of dense granule secretion via deficiency for MUNC13-4, which is required for exocytosis in platelets, similarly impaired the ability of platelets to enhance tumor cell transmigration. Furthermore, MUNC13-4 loss diminished metastasis formation without affecting primary tumor growth, suggesting that platelet-mediated ATP secretion promotes opening of the endothelial barrier to enable cancer cell extravasation. Consistent with this idea, deficiency for P2Y2, a purinergic receptor that is activated by adenine nucleotides and expressed on endothelial cells, prevented increased endothelial cell permeability and tumor cell transmigration in response to platelet secretion of ATP, resulting in reduced cancer cell extravasation and decreased metastasis formation in vivo. These findings identify a critical role for adenine nucleotide secretion by platelets and ATP-dependent activation of endothelial P2Y2 receptors in tumor cell extravasation and suggest that inhibition of P2Y2 receptors may limit metastatic spread without interfering with normal platelet functions.