Secreted cathepsin L generates endostatin from collagen XVIII

Endostatin, an inhibitor of angiogenesis and tumor growth, was identified o riginally in conditioned media of murine hemangioendothelioma (EOMA) cells. N-terminal amino acid sequencing demonstrated that it corresponds to a fra gment of basement membrane collagen XVIII. Here we report that cathepsin L is secreted by EOMA cells and is responsible for the generation of endostat in with the predicted N-terminus, while metalloproteases produce larger fra gments in a parallel processing pathway. Efficient endostatin generation re quires a moderately acidic pH similar to the pericellular milieu of tumors. The secretion of cathepsin L by a tumor cell line of endothelial origin su ggests that this cathepsin may play a role in angiogenesis. We propose that cleavage within collagen XVIII's protease-sensitive region evolved to regu late excessive proteolysis in conditions of induced angiogenesis.