title: Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo.
abstract: 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.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, TN 37232, USA.
authors.forename: Dana M
authors.initials: DM
authors.lastname: Brantley
authors.forename: Nikki
authors.initials: N
authors.lastname: Cheng
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Thompson
authors.forename: Qing
authors.initials: Q
authors.lastname: Lin
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Brekken
authors.forename: Philip E
authors.initials: PE
authors.lastname: Thorpe
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Muraoka
authors.forename: Douglas Pat
authors.initials: DP
authors.lastname: Cerretti
authors.forename: Ambra
authors.initials: A
authors.lastname: Pozzi
authors.forename: Dowdy
authors.initials: D
authors.lastname: Jackson
authors.forename: Charles
authors.initials: C
authors.lastname: Lin
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
mesh_terms: D007516:Adenoma, Islet Cell / Q000098:blood supply; D000818:Animals; D002465:Cell Movement; D016228:Endothelial Growth Factors / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D020287:In Situ Nick-End Labeling; D008222:Lymphokines / Q000502:physiology; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D036082:Receptor, EphA1; D036104:Receptor, EphA2; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D008222:Lymphokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018809:Proliferating Cell Nuclear Antigen; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D036082:Receptor, EphA1; D036104:Receptor, EphA2