The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin

Stephen Gately, Przemyslaw Twardowski, M. Sharon Stack, Deborah L. Cundiff, Davida Grella, Francis J. Castellino, Jan Enghild, Hau C. Kwaan, Francis Lee, Robert A. Kramer, Olga Volpert, Noel Bouck, Gerald A. Soff*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

269 Scopus citations

Abstract

Angiostatin, a potent naturally occurring inhibitor of angiogenesis and growth of tumor metastases, is generated by cancer-mediated proteolysis of plasminogen. Human prostate carcinoma cells (PC-3) release enzymatic activity that converts plasminogen to angiostatin. We have now identified two components released by PC-3 cells, urokinase (uPA) and free sulfhydryl donors (FSDs), that are sufficient for angiostatin generation. Furthermore, in a defined cell-free system, plasminogen activators [uPA, tissue-type plasminogen activator (tPA), or streptokinase], in combination with one of a series of FSDs (N-acetyl-L-cysteine, D-penicillamine, captopril, L-cysteine, or reduced glutathione] generate angiostatin from plasminogen. An essential role of plasmin catalytic activity for angiostatin generation was identified by using recombinant mutant plasminogens as substrates. The wild-type recombinant plasminogen was converted to angiostatin in the setting of uPA/FSD; however, a plasminogen activation site mutant and a catalytically inactive mutant failed to generate angiostatin. Cell-free derived angiostatin inhibited angiogenesis in vitro and in vivo and suppressed the growth of Lewis lung carcinoma metastases. These findings define a direct mechanism for cancer-cell-mediated angiostatin generation and permit large-scale production of bioactive angiostatin for investigation and potential therapeutic application.

Original languageEnglish (US)
Pages (from-to)10868-10872
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number20
DOIs
StatePublished - Sep 30 1997

ASJC Scopus subject areas

  • General

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