The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin Academic Article Article uri icon

Overview

MeSH Major

  • Anticoagulants
  • Drugs, Generic
  • Enoxaparin
  • Skin

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.

publication date

  • September 30, 1997

Research

keywords

  • Academic Article

Identity

Digital Object Identifier (DOI)

  • 10.1073/pnas.94.20.10868

PubMed ID

  • 9380726

Additional Document Info

start page

  • 10868

end page

  • 72

volume

  • 94

number

  • 20