Impaired tumor microenvironment in EphA2-deficient mice inhibits tumor angiogenesis and metastatic progression

ABSTRACTEphA2 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.