ANGIOSTATIN - A NOVEL ANGIOGENESIS INHIBITOR THAT MEDIATES THE SUPPRESSION OF METASTASES BY A LEWIS LUNG-CARCINOMA

The phenomenon of inhibition of tumor growth by tumor mass has been re peatedly studied, but without elucidation of a satisfactory mechanism. In our animal model, a primary tumor inhibits its remote metastases. After tumor removal, metastases neovascularize and grow. When the prim ary tumor is present, metastatic growth is suppressed by a circulating angiogenesis inhibitor. Serum and urine from tumor-bearing mice, but not from controls, specifically inhibit endothelial cell proliferation . The activity copurifies with a 38 kDa plasminogen fragment that we h ave sequenced and named angiostatin. A corresponding fragment of human plasminogen has similar activity. Systemic administration of angiosta tin, but not intact plasminogen, potently blocks neovascularization an d growth of metastases. We here show that the inhibition of metastases by a primary mouse tumor is mediated, at least in part, by angiostati n.