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.