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 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.
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GA
Division of Hematology/Oncology, Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Sanderowitz
J
J
Gately
S
S
Verrusio
E
E
Weiss
I
I
Brem
S
S
Kwaan
H C
HC
D000818:Animals; D002460:Cell Line; D002999:Clone Cells; D015870:Gene Expression; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D008175:Lung Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D001616:beta-Galactosidase / Q000032:analysis / Q000096:biosynthesis
D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D001616:beta-Galactosidase