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

Expression of urokinase-type plasminogen activator (uPA) by malignant cells correlates with an aggressive phenotype, including increased inv asiveness, tumor-associated angiogenesis, and metastases, Plasminogen activator inhibitor type 1 (PAI-1) is undetectable in cells of some ag gressive malignancies, but present in the stroma of tumor-associated m icrovasculature, This analysis of an athymic mouse model of prostate c arcinoma further defines the role of the uPA/PAI-1/plasmin system in p rimary growth and metastasis. A marked increase in PAI-1 expression wa s induced in clones of the aggressive human prostate carcinoma line, P C-3, by stable transfection. Primary PC-3 tumors, in mice, were signif icantly smaller when derived from PAI-1 expressing versus control cell s, PAI-1 expression reduced the density of tumor-associated microvascu lature by 22-38%, Microscopic metastases were quantitated using stable expression of the chromogenic label (beta-galactosidase) in control a nd 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 o r molecular inhibition of uPA activity as a potential therapeutic targ et.