Key Roles for the Lipid Signaling Enzyme Phospholipase D1 in the Tumor Microenvironment During Tumor Angiogenesis and Metastasis

Angiogenesis inhibitors, which target tumor cells, confer only short-term benefits on tumor growth. We report that ablation of the lipid signaling enzyme phospholipase D1 (PLD1) in the tumor environment compromised the neovascularization and growth of tumors. PLD1 deficiency suppressed the activation of Akt and mitogen-activated protein kinase signaling pathways by vascular endothelial growth factor in vascular endothelial cells, resulting in decreased integrin-dependent cell adhesion to, and migration on, extracellular matrices, as well as reduced tumor angiogenesis in a xenograft model. In addition, mice lacking PLD1 incurred fewer lung metastases than did wild-type mice. Bone marrow transplantation and binding studies identified a platelet-derived mechanism involving decreased tumor cell-platelet interactions, in part because of impaired activation of alpha(IIb)beta(3) integrin in platelets, which decreased the seeding of tumor cells into the lung parenchyma. Treatment with a small-molecule inhibitor of PLD1 phenocopied PLD1 deficiency, efficiently suppressing both tumor growth and metastasis in mice. These findings reveal that PLD1 in the tumor environment promotes tumor growth and metastasis and, taken together with previous reports on the roles of PLD in tumor cell-intrinsic adaptations to stress, suggest the potential use of PLD inhibitors as cancer therapeutics.