Expression of plasminogen activator inhibitor-2 in epithelial ovarian cancer: a favorable prognostic factor related to the actions of CSF-1.
In ovarian cancer cells, the macrophage colony-stimulating factor-1 (CSF-1) induces the release of plasminogen activator inhibitor-2 (PAI-2), and high levels of PAI-2 as well as of CSF-1 in ovarian cancer ascites are independently correlated with poor outcome. We now study the effect of CSF-1 on PAI-2 expression in vitro and the significance of cellular PAI-2 expression in vivo. Immunohistochemical detection of PAI-2 was studied in primary and metastatic tissues from 130 epithelial ovarian cancer cases. Kaplan-Meier curves of survival were compared with the results of log-rank test. The Cox regression model was used for multivariate analysis. The effect of CSF-1 on PAI-2 expression in ovarian cancer cells was also examined in vitro. Fifty-eight percent of the primary tumors and 68% of the metastases expressed PAI-2. PAI-2 expression in the metastases of invasive stages III and IV cases was strongly predictive of a prolonged disease-free and overall survival. This finding was associated with low residual disease and was also an independent factor for disease-free survival. In vitro, CSF-1 treatment of ovarian cancer cells resulted in a decrease in cellular staining for PAI-2 while increasing the release of PAI-2 into the conditioned medium. In vivo, we also found an inverse correlation between expression of CSF-1 and that of PAI-2 in the primary tumors. We thus describe the favorable independent prognosis of cellular PAI-2 expression in the metastases of ovarian cancer. Moreover, an inverse correlation was observed between CSF-1 and PAI-2 expression in vivo. This lends support for a primary role of cell-surface (vs. secreted)-mediated events of plasminogen activation in the development of invasive, poor prognostic phenotypes.
Chambers
S K
SK
Department of Obstetrics and Gynecology, Yale University, School of Medicine, New Haven, CT 06520-8063, USA.
Ivins
C M
CM
Carcangiu
M L
ML
D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D017396:Plasminogen Activator Inhibitor 2 / Q000096:biosynthesis*; D011379:Prognosis; D014407:Tumor Cells, Cultured / Q000187:drug effects
D017396:Plasminogen Activator Inhibitor 2; D016173:Macrophage Colony-Stimulating Factor