Proteolytic Exposure of a Cryptic Site within Collagen Type IV Is Required for Angiogenesis and Tumor Growth in vivo

• Published in: The Journal of cell biology 2001-09, Vol.154 (5), p.1069-1079
• Main Authors: Xu, Jingsong, Rodriguez, Dorothy, Petitclerc, Eric, Kim, Jenny J., Hangai, Masanori, Yuen, S. Moon, Davis, George E., Brooks, Peter C.
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Antibodies; Antibodies, Monoclonal - metabolism; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Basement Membrane - chemistry; Basement Membrane - metabolism; Binding Sites; Blood vessels; Cell adhesion; Cell Adhesion - physiology; Cell Movement - physiology; Cellular biology; Chick Embryo; Collagen - chemistry; Collagen - immunology; Collagen - metabolism; Collagens; Corneal Neovascularization - chemically induced; Diabetic Retinopathy - metabolism; Diabetic Retinopathy - pathology; Endothelial cells; Endothelium, Vascular - metabolism; Epitopes; Epitopes - metabolism; Humans; Integrins; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Melanoma; Melanoma - blood supply; Melanoma - pathology; Mice; Microscopy, Fluorescence; Molecules; Neoplasm Transplantation; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Neovascularization, Pathologic; Neovascularization, Physiologic; Peptide Hydrolases - metabolism; Protein Binding; Protein Denaturation; Protein Structure, Tertiary; Rats; Receptors, Vitronectin - metabolism; Retinal Vessels - metabolism; Skin - blood supply; Skin - metabolism; Tumor Cells, Cultured; Tumors
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200103111

Evidence is provided that proteolytic cleavage of collagen type IV results in the exposure of a functionally important cryptic site hidden within its triple helical structure. Exposure of this cryptic site was associated with angiogenic, but not quiescent, blood vessels and was required for angiogenesis in vivo. Exposure of the HUIV26 epitope was associated with a loss of α1β1 integrin binding and the gain of αvβ3 binding. A monoclonal antibody (HUIV26) directed to this site disrupts integrin-dependent endothelial cell interactions and potently inhibits angiogenesis and tumor growth. Together, these studies suggest a novel mechanism by which proteolysis contributes to angiogenesis by exposing hidden regulatory elements within matrix-immobilized collagen type IV.