New functions for non-collagenous domains of human collagen type IV. Novel integrin ligands inhibiting angiogenesis and tumor growth in vivo.
Collagen type IV is a major component of the basal lamina of blood vessels. Six genetically distinct collagen type IV chains have been identified and are distributed in a tissue-specific manner. Here we define a novel function for soluble non-collagenous (NC1) domains of the alpha2(IV), alpha3(IV), and alpha6(IV) chains of human collagen type IV in the regulation of angiogenesis and tumor growth. These NC1 domains were shown to regulate endothelial cell adhesion and migration by distinct alpha(v) and beta(1) integrin-dependent mechanisms. Systemic administration of recombinant alpha2(IV), alpha3(IV), and alpha6(IV) NC1 domains potently inhibit angiogenesis and tumor growth, whereas alpha1(IV), alpha4(IV), and alpha5(IV) showed little if any effect. These findings suggest that specific NC1 domains of collagen type IV may represent an important new class of angiogenesis inhibitors.
Petitclerc
E
E
Department of Biochemistry and Molecular Biology, University of Southern California School of Medicine, Los Angeles, California 90033, USA.
Boutaud
A
A
Prestayko
A
A
Xu
J
J
Sado
Y
Y
Ninomiya
Y
Y
Sarras
M P
MP
Hudson
B G
BG
Brooks
P C
PC
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001485:Basement Membrane / Q000378:metabolism; D002277:Carcinoma / Q000098:blood supply; D002448:Cell Adhesion; D002642:Chick Embryo; D003094:Collagen / Q000378:metabolism / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology; D005321:Extraembryonic Membranes / Q000098:blood supply; D006801:Humans; D039564:Integrin alphaV; D019012:Integrin beta1 / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D008024:Ligands; D008545:Melanoma / Q000098:blood supply; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D001749:Urinary Bladder Neoplasms / Q000098:blood supply
D020533:Angiogenesis Inhibitors; D015703:Antigens, CD; D039564:Integrin alphaV; D019012:Integrin beta1; D016023:Integrins; D008024:Ligands; D010446:Peptide Fragments; D003094:Collagen