Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo.

Brantley DM, Cheng N, Thompson EJ, Lin Q, Brekken RA, Thorpe PE, Muraoka RS, Cerretti DP, Pozzi A, Jackson D, Lin C, Chen J
Oncogene. 2002 21 (46): 7011-26

PMID: 12370823 · DOI:10.1038/sj.onc.1205679

The Eph family of receptor tyrosine kinases and their ligands, known as ephrins, play a crucial role in vascular development during embryogenesis. The function of these molecules in adult angiogenesis has not been well characterized. Here, we report that blocking Eph A class receptor activation inhibits angiogenesis in two independent tumor types, the RIP-Tag transgenic model of angiogenesis-dependent pancreatic islet cell carcinoma and the 4T1 model of metastatic mammary adenocarcinoma. Ephrin-A1 ligand was expressed in both tumor and endothelial cells, and EphA2 receptor was localized primarily in tumor-associated vascular endothelial cells. Soluble EphA2-Fc or EphA3-Fc receptors inhibited tumor angiogenesis in cutaneous window assays, and tumor growth in vivo. EphA2-Fc or EphA3-Fc treatment resulted in decreased tumor vascular density, tumor volume, and cell proliferation, but increased cell apoptosis. However, EphA2-Fc had no direct effect on tumor cell growth or apoptosis in culture, yet inhibited migration of endothelial cells in response to tumor cells, suggesting that the soluble receptor inhibited blood vessel recruitment by the tumor. These data provide the first functional evidence for Eph A class receptor regulation of pathogenic angiogenesis induced by tumors and support the function of A class Eph receptors in tumor progression.

MeSH Terms (22)

Adenoma, Islet Cell Animals Cell Movement Endothelial Growth Factors Endothelium, Vascular Female In Situ Nick-End Labeling Lymphokines Mammary Neoplasms, Experimental Mice Mice, Inbred BALB C Mice, Inbred C57BL Neoplasms, Experimental Neovascularization, Pathologic Platelet Endothelial Cell Adhesion Molecule-1 Proliferating Cell Nuclear Antigen Receptor, EphA1 Receptor, EphA2 Receptor Protein-Tyrosine Kinases Tumor Cells, Cultured Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors

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