Impaired tumor microenvironment in EphA2-deficient mice inhibits tumor angiogenesis and metastatic progression.
EphA2 belongs to a unique family of receptor tyrosine kinases that play critical roles in development and disease. Since EphA2 is required for ephrin-A1 ligand-induced vascular remodeling and is overexpressed in a variety of vascularized human adenocarcinomas, we assessed tumor angiogenesis and metastatic progression in EphA2-deficient host animals. 4T1 metastatic mammary adenocarcinoma cells transplanted subcutaneously and orthotopically into EphA2-deficient female mice displayed decreased tumor volume, tumor cell survival, microvascular density, and lung metastasis relative to tumor-bearing littermate controls. To determine if the phenotype in EphA2-deficient mice was endothelial cell intrinsic, we also analyzed endothelial cells isolated from EphA2-deficient animals for their ability to incorporate into tumor vessels in vivo, as well as to migrate in response to tumor-derived signals in vitro. EphA2-deficient endothelial cells displayed impaired survival and failed to incorporate into tumor microvessels in vivo, and displayed impaired tumor-mediated migration in vitro relative to controls. These data suggest that host EphA2 receptor tyrosine kinase function is required in the tumor microenvironment for tumor angiogenesis and metastatic progression.
Brantley-Sieders
Dana M
DM
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2363, USA.
Fang
Wei Bin
WB
Hicks
Donna J
DJ
Zhuang
Guanglei
G
Shyr
Yu
Y
Chen
Jin
J
D000230:Adenocarcinoma / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D017690:Cell Transplantation; D003094:Collagen / Q000737:chemistry; D018450:Disease Progression; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000473:pathology; D036382:Ephrin-A1 / Q000378:metabolism; D005260:Female; D020287:In Situ Nick-End Labeling; D007763:Lac Operon; D007797:Laminin / Q000737:chemistry; D008024:Ligands; D008168:Lung / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000098:blood supply* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D008833:Microcirculation; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D015233:Models, Statistical; D009154:Mutation; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D011509:Proteoglycans / Q000737:chemistry; D036104:Receptor, EphA2 / Q000235:genetics* / Q000502:physiology*; D036081:Receptors, Eph Family / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D004338:Drug Combinations; D036382:Ephrin-A1; D007797:Laminin; D008024:Ligands; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen; D036104:Receptor, EphA2; D036081:Receptors, Eph Family; D020830:rac1 GTP-Binding Protein; D010100:Oxygen