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

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  • S Gately, Denmark
  • P Twardowski, Denmark
  • M S Stack, Denmark
  • D L Cundiff, Denmark
  • D Grella, Denmark
  • F J Castellino, Denmark
  • J Enghild
  • H C Kwaan, Denmark
  • F Lee, Denmark
  • R A Kramer, Denmark
  • O Volpert, Denmark
  • N Bouck, Denmark
  • G A Soff, Denmark
  • Interdisciplinary Nanoscience Center
  • Department of Molecular Biology
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
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue20
Pages (from-to)10868-72
Number of pages4
ISSN0027-8424
Publication statusPublished - 1997

    Research areas

  • Angiostatins, Animals, Antineoplastic Agents, Carcinoma, Lewis Lung, Cell-Free System, Chromatography, Affinity, Humans, Male, Mice, Mice, Inbred C57BL, Neovascularization, Pathologic, Peptide Fragments, Plasminogen, Prostatic Neoplasms

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