A critical role of EphA2 receptor tyrosine kinase in tumor angiogenesis and metastasis

6133 EphA2 receptor belongs to a unique family of tyrosine kinases (RTK) that mediate cell-cell adhesion/repulsion, cell-matrix adhesion, and cell migration. EphA2 is overexpressed in both breast tumor cells and blood vessel endothelial cells in the host environment in more than 70% of clinical breast cancer specimens. In addition, a high level of EphA2 expression consistently correlates with a high degree of tumor malignancy. To determine the role of EphA2 receptor in tumor neovascular growth, we initially blocked A-class Eph receptor tyrosine kinase activation by soluble EphA2-Fc or EphA3-Fc receptors. These soluble receptors inhibited 4T1 mammary tumor progression in vivo, providing the first functional evidence of EphA receptor involvement in breast tumor angiogenesis. To determine the specific role of EphA2 receptor in tumor angiogenesis, we characterized EphA2-deficient mice. EphA2-null endothelial cells (ECs) fail to undergo vascular assembly and migration in vitro and angiogenesis in vivo, and are defective in PI3K-dependent Rac1 GTPase activation in response to ligand stimulation. Loss of EphA2 receptor in the host significantly inhibited tumor volume, neovascularization and metastasis of orthotopically grafted 4T1 mammary tumors. In addition, EphA2-deficient ECs fail to migrate, coalesce, and incorporate into tumor blood vessels when co-transplanted with 4T1 tumor cells, indicating an EC-specific defect in tumor neovascularization. Taken together, these data suggest that host EphA2 receptor function is required in the tumor microenvironment for tumor angiogenesis and metastatic progression. Our findings are novel and significant in several respects. First, our data presented here, together with studies from other laboratories, indicate that EphA2 plays a key role in breast tumor progression through both tumor and host-dependent mechanisms. Because this single factor influences tumor progression in both tumor cells and tumor blood vessels, EphA2 receptor is an attractive target for the development of new treatments for breast cancer. Second, EphA2 receptor appears not to be required for embryonic development, but is critical in adult angiogenesis and cancer and thus targeted inhibition of EphA2 receptor should have limited side effects to normal tissue. Finally, the new mouse model of EphA2 deficient mice provides a novel tool to dissect the function of EphA2 in tumor cells and tumor endothelium in vivo in clinically relevant breast cancer models.