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.