Angiostatin: an endogenous inhibitor of angiogenesis and of tumor growth.
Angiostatin, an internal fragment of plasminogen, is a potent inhibitor of angiogenesis, which selectively inhibits endothelial cell proliferation. When given systemically, angiostatin potently inhibits tumor growth and can maintain metastatic and primary tumors in a dormant state defined by a balance of proliferation and apoptosis of the tumor cells. We identified angiostatin while studying the phenomenon of inhibition of tumor growth by tumor mass and have elucidated one mechanism for this phenomenon. In our animal model, a primary tumor almost completely suppresses the growth of its remote metastases. However, after tumor removal, the previously dormant metastases neovascularize and grow. When the primary 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 kD plasminogen fragment which we have sequenced and named angiostatin. Human angiostatin, obtained from a limited proteolytic digest of human plasminogen, has similar activities. Systemic administration of angiostatin, but not intact plasminogen, potently blocks neovascularization and growth of metastases and primary tumors. We here show that the inhibition of metastases by a primary mouse tumor is mediated, at least in part, by the angiogenesis inhibitor angiostatin.
O'Reilly
M S
MS
Department of Surgery, Children's Hospital, Boston, Massachusetts, USA.
D043168:Angiostatins; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D003315:Cornea / Q000098:blood supply; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D006801:Humans; D051379:Mice; D008961:Models, Structural; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology*; D010958:Plasminogen / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology*
D000970:Antineoplastic Agents; D010446:Peptide Fragments; D043168:Angiostatins; D010958:Plasminogen