Ephrin-A1 facilitates mammary tumor metastasis through an angiogenesis-dependent mechanism mediated by EphA receptor and vascular endothelial growth factor in mice.
Ephrin-A1, the prototypic ligand for EphA receptor tyrosine kinases, is overexpressed in vascularized tumors relative to normal tissue. Moreover, ephrin-A1-Fc fusion proteins induce endothelial cell sprouting, migration, and assembly in vitro, and s.c. vascular remodeling in vivo. Based on these data, we hypothesized that native, membrane-bound ephrin-A1 regulates tumor angiogenesis and progression. We tested this hypothesis using a transplantable mouse mammary tumor model. Small interfering RNA-mediated ephrin-A1 knockdown in metastatic mammary tumor cells significantly diminishes lung metastasis without affecting tumor volume, invasion, intravasation, or lung colonization upon i.v. injection in vivo. Ephrin-A1 knockdown reduced tumor-induced endothelial cell migration in vitro and microvascular density in vivo. Conversely, overexpression of ephrin-A1 in nonmetastatic mammary tumor cells elevated microvascular density and vascular recruitment. Overexpression of ephrin-A1 elevated wild-type but not EphA2-deficient endothelial cell migration toward tumor cells, suggesting that activation of EphA2 on endothelial cells is one mechanism by which ephrin-A1 regulates angiogenesis. Furthermore, ephrin-A1 knockdown diminished, whereas overexpression of ephrin-A1 elevated, vascular endothelial growth factor (VEGF) levels in tumor cell-conditioned medium, suggesting that ephrin-A1-mediated modulation of the VEGF pathway is another mechanism by which membrane-tethered ephrin-A1 regulates angiogenic responses from initially distant host endothelium. These data suggest that ephrin-A1 is a proangiogenic signal, regulating VEGF expression and facilitating angiogenesis-dependent metastatic spread.
Brantley-Sieders
Dana M
DM
Division of Rheumatology and Immunology, Department of Medicin, Vanderbilt University School of Medicine, Nashville, TN 37232-2363, USA.
Fang
Wei Bin
WB
Hwang
Yoonha
Y
Hicks
Donna
D
Chen
Jin
J
D000230:Adenocarcinoma / Q000098:blood supply* / Q000556:secondary; D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology; D036382:Ephrin-A1 / Q000502:physiology*; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000209:etiology*; D036081:Receptors, Eph Family / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
D036382:Ephrin-A1; D042461:Vascular Endothelial Growth Factor A; D036081:Receptors, Eph Family