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

S Kim, K Bell, SA Mousa, JA Varner - The American journal of pathology, 2000 - Elsevier
S Kim, K Bell, SA Mousa, JA Varner
The American journal of pathology, 2000Elsevier
Angiogenesis depends on the cooperation of growth factors and cell adhesion events.
Although αv integrins have been shown to play critical roles in angiogenesis, recent studies
in αv-null mice suggest that other adhesion receptors and their ligands also regulate this
process. Evidence is now provided that the integrin α5β1 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 …
Angiogenesis depends on the cooperation of growth factors and cell adhesion events. Although αv integrins have been shown to play critical roles in angiogenesis, recent studies in αv-null mice suggest that other adhesion receptors and their ligands also regulate this process. Evidence is now provided that the integrin α5β1 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 α5β1-dependent manner. Importantly, antibody, peptide, and novel nonpeptide antagonists of integrin α5β1 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 α5β1 antagonists inhibited tumor angiogenesis, thereby causing regression of human tumors in animal models. Thus, fibronectin and integrin α5β1, like integrin αvβ3, contribute to an angiogenesis pathway that is distinct from VEGF-mediated angiogenesis, yet important for the growth of tumors.
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