Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth

We isolated and identified an endogenous 24-kDa human basement membrane-der ived inhibitor of angiogenesis and tumor growth, termed canstatin, Canstati n, a fragment of the alpha 2 chain of type TV collagen, was produced as a r ecombinant molecule in Escherichia coli and 293 embryonic kidneys cells. Ca nstatin significantly inhibited human endothelial cell migration and murine endothelial cell tube formation. Additionally, canstatin potently inhibite d 10% fetal bovine serum-stimulated endothelial cell proliferation and indu ced apoptosis, with no inhibition of proliferation or apoptosis observed on non-endothelial cells. Inhibition of endothelial proliferation was not con comitant with a change in extracellular signal-regulated kinase activation. We demonstrate that apoptosis induced by canstatin was associated with a d own-regulation of the anti-apoptotic protein, FLIP. Canstatin also suppress ed in vivo growth of large and small size tumors in two human xenograft mou se models with histology revealing decreased CD31-positive vasculature. Col lectively, these results suggest that canstatin is a powerful therapeutic m olecule for suppressing angiogenesis.