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 alpha 2(TV), alpha 3(IV), and alpha 6(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 alpha 2(IV), alpha 3(IV), and alpha 6(IV) NC1 domains potently inhibit angiogenesis and tumor growth, whereas alpha 1(TV), alpha 4(TV), and alpha 5(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.