Proteolytic exposure of a cryptic site within collagen type IV is required for angiogenesis and tumor growth in vivo.
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 alpha1beta1 integrin binding and the gain of alphavbeta3 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.
Xu
J
J
Department of Radiation Oncology, Kaplan Cancer Center, New York University School of Medicine, New York, NY 10016, USA.
Rodriguez
D
D
Petitclerc
E
E
Kim
J J
JJ
Hangai
M
M
Moon
Y S
YS
Davis
G E
GE
Brooks
P C
PC
Yuen
S M
SM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D001485:Basement Membrane / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002642:Chick Embryo; D003094:Collagen / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D016510:Corneal Neovascularization / Q000139:chemically induced; D003930:Diabetic Retinopathy / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism; D000939:Epitopes / Q000378:metabolism; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000098:blood supply / Q000473:pathology; D051379:Mice; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D010447:Peptide Hydrolases / Q000378:metabolism; D011485:Protein Binding; D011489:Protein Denaturation; D017434:Protein Structure, Tertiary; D051381:Rats; D019030:Receptors, Vitronectin / Q000378:metabolism; D012171:Retinal Vessels / Q000378:metabolism; D012867:Skin / Q000098:blood supply / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000939:Epitopes; D019030:Receptors, Vitronectin; D003094:Collagen; D010447:Peptide Hydrolases; D020778:Matrix Metalloproteinase 2