The generation of endostatin is mediated by elastase

Endostatin, a potent inhibitor of angiogenesis and tumor growth, is a COOH- terminal fragment of collagen XVIII derived through cleavage of an Ala-His linkage by an as yet unidentified endostatin-processing enzyme, Endostatin was originally isolated from the conditioned medium of hemangioendothelioma (EOMA) cells. By investigating the processing of collagen XVIII to endosta tin by EOMA cells, we show here that the generation of endostatin can be me diated by an elastase activity. We also show that several members of the el astase family can act as an endostatin-processing enzyme by specifically cl eaving the Ala-His linkage and releasing endostatin from a precursor molecu le, We further suggest that the generation of endostatin from collagen XVII I is at least a two-step process, involving a metal-dependent early step an d an elastase activity-dependent final step.