Expression of plasminogen activator inhibitor type 1 by human prostate carcinoma cells inhibits primary tumor growth, tumor-associated angiogenesis, and metastasis to lung and liver in an athymic mouse model

Gerald A. Soff, Judith Sanderowitz, Stephen Gately, Elaine Verrusio, Ivy Weiss, Steven Brem, Hau C. Kwaan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

152 Scopus citations

Abstract

Expression of urokinase-type plasminogen activator (uPA) by malignant cells correlates with an aggressive phenotype, including increased invasiveness, tumor-associated angiogenesis, and metastases. Plasminogen activator inhibitor type 1 (PAI-1) is undetectable in cells of some aggressive malignancies, but present in the stroma of tumor-associated microvasculature. This analysis of an athymic mouse model of prostate carcinoma further defines the role of the uPA/ PAI-1/plasmin system in primary growth and metastasis. A marked increase in PAI-1 expression was induced in clones of the aggressive human prostate carcinoma line, PC-3, by stable transfection. Primary PC-3 tumors, in mice, were significantly smaller when derived from PAI-1 expressing versus control cells. PAI-1 expression reduced the density of tumor-associated microvasculature by 22-38%. Microscopic metastases were quantitated using stable expression of the chromogenic label (β-galactosidase) in control and PAI-1 expressing cells. PAI-1 expression resulted in a significant inhibition of lung metastases, and liver metastases. Expression of PAI-1 by malignant prostate cells resulted in a less aggressive phenotype, presumably by inhibition of uPA activity, suggesting pharmacologic or molecular inhibition of uPA activity as a potential therapeutic target.

Original languageEnglish (US)
Pages (from-to)2593-2600
Number of pages8
JournalJournal of Clinical Investigation
Volume96
Issue number6
DOIs
StatePublished - Dec 1995

Keywords

  • β-galactosidase
  • Metastases
  • Plasminogen activator inhibitor type 1
  • Prostate carcinoma
  • Urokinase type plasminogen activator

ASJC Scopus subject areas

  • Medicine(all)

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