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

被引:139
作者
Soff, GA
Sanderowitz, J
Gately, S
Verrusio, E
Weiss, I
Brem, S
Kwaan, HC
机构
[1] NORTHWESTERN UNIV,SCH MED,DEPT MED,DIV HEMATOL ONCOL,CHICAGO,IL 60611
[2] NORTHWESTERN UNIV,SCH MED,DEPT SURG,DIV NEUROSURG,CHICAGO,IL 60611
关键词
prostate carcinoma; plasminogen activator inhibitor type 1; urokinase type plasminogen activator; metastases; beta-galactosidase;
D O I
10.1172/JCI118323
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:2593 / 2600
页数:8
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