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

J Clin Invest. 1995 Dec;96(6):2593-600. doi: 10.1172/JCI118323.


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 (beta-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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Clone Cells
  • Gene Expression
  • Humans
  • Liver Neoplasms / blood supply
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Liver Neoplasms / secondary*
  • Lung Neoplasms / blood supply
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Lung Neoplasms / secondary*
  • Male
  • Mice
  • Mice, Nude
  • Neovascularization, Pathologic*
  • Plasminogen Activator Inhibitor 1 / biosynthesis*
  • Prostatic Neoplasms / blood supply
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology*
  • RNA, Messenger / biosynthesis
  • Transfection
  • Transplantation, Heterologous
  • Tumor Cells, Cultured
  • beta-Galactosidase / analysis
  • beta-Galactosidase / biosynthesis


  • Plasminogen Activator Inhibitor 1
  • RNA, Messenger
  • beta-Galactosidase