Regulation of angiogenesis in vivo by ligation of integrin α5β1 with the central cell-binding domain of fibronectin

Angiogenesis depends on the cooperation of growth factors and cell adhesion events, Although alpha v integrins have been shown to play critical roles in angiogenesis, recent studies in alpha-null mice suggest that other adhesion receptors and their ligands also regulate this process. Evidence is now provided that the integrin alpha 5 beta 1 and its ligand fibronectin are coordinately up-regulated on blood vessels in human tumor biopsies and play critical roles in angiogenesis, resulting in tumor growth in vivo. Angiogenesis induced by multiple growth factors in chick embryos was blocked by monoclonal antibodies to the cell-binding domain of fibronectin. Furthermore, application of fibronectin or a proteolytic fragment of fibronectin containing the central cell-binding domain to the chick chorioallantoic membrane enhanced angiogenesis in an integrin alpha 5 beta 1-dependent manner, Importantly, antibody, peptide, and novel nonpeptide antagonists of integrin alpha 5 beta 1 blocked angiogenesis induced by several growth factors but had little effect on angiogenesis induced by vascular endothelial growth factor (VEGF) in both chick embryo and murine models, In fact, these alpha 5 beta 1 antagonists inhibited tumor angiogenesis, thereby causing regression of human tumors in animal models. Thus, fibronectin and integrin alpha 5 beta 1, like integrin alpha v beta 3, contribute to an angiogenesis pathway that is distinct from VEGF-mediated angiogenesis, yet important for the growth of tumors.