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

Abstract

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.

• Authors: Dana M Brantley-Sieders, Wei Bin Fang, Donna J Hicks, Guanglei Zhuang, Yu Shyr, Jin Chen
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 19 Issue 13 Pg. 1884-6 (Nov 2005) ISSN: 1530-6860 [Electronic] United States
• PMID: 16166198 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Drug Combinations
• Ephrin-A1
• Laminin
• Ligands
• Platelet Endothelial Cell Adhesion Molecule-1
• Proteoglycans
• matrigel
• Collagen
• Receptor, EphA2
• Receptors, Eph Family
• rac1 GTP-Binding Protein
• Oxygen

Topics

• Adenocarcinoma (metabolism)
• Animals
• Breast Neoplasms (pathology)
• Cell Line, Tumor
• Cell Movement
• Cell Survival
• Cell Transplantation
• Collagen (chemistry)
• Disease Progression
• Drug Combinations
• Endothelium, Vascular (pathology)
• Ephrin-A1 (metabolism)
• Female
• In Situ Nick-End Labeling
• Lac Operon
• Laminin (chemistry)
• Ligands
• Lung (pathology)
• Mammary Neoplasms, Animal (blood supply, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mice, Transgenic
• Microcirculation
• Microscopy, Fluorescence
• Models, Biological
• Models, Statistical
• Mutation
• Neoplasm Metastasis
• Neoplasm Transplantation
• Neovascularization, Pathologic
• Oxygen (metabolism)
• Phenotype
• Platelet Endothelial Cell Adhesion Molecule-1 (biosynthesis)
• Proteoglycans (chemistry)
• Receptor, EphA2 (genetics, physiology)
• Receptors, Eph Family (metabolism)
• rac1 GTP-Binding Protein (metabolism)