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PMID: 9380726 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 94 ·No. 20 ·1997-09-30 ·Pages 10868-72

Gately S, Twardowski P, Stack MS, Cundiff DL, Grella D, Castellino FJ, Enghild J, Kwaan HC, Lee F, Kramer RA, Volpert O, Bouck N, Soff GA

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.

MeSH Terms
Angiostatins Animals Antineoplastic Agents/metabolism Carcinoma, Lewis Lung/metabolism,pathology Cell-Free System Chromatography, Affinity Humans Male Mice Mice, Inbred C57BL Neovascularization, Pathologic/prevention & control Peptide Fragments/biosynthesis,isolation & purification Plasminogen/biosynthesis,isolation & purification,metabolism Prostatic Neoplasms/metabolism,pathology
Chemicals
Antineoplastic Agents Peptide Fragments Angiostatins Plasminogen
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Gately S
Department of Medicine, Division of Hematology/Oncology, Northwestern University School of Medicine, Chicago, IL 60611, USA.
Twardowski P
Stack M S
Cundiff D L
Grella D
Castellino F J
Enghild J
Kwaan H C
Lee F
Kramer R A
Volpert O
Bouck N
Soff G A
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.94.20.10868
Published
1997-09-30
Pages
10868-72
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC23512
Subset
IM
Grants
NCI NIH HHS · CA71875 · United States
NHLBI NIH HHS · R37 HL013423 · United States
NHLBI NIH HHS · R01 HL013423 · United States
NCI NIH HHS · CA58900 · United States
NHLBI NIH HHS · HL13423 · United States
External Links
PubMed source DOI: 10.1073/pnas.94.20.10868 PMC Full Text View journal details
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