The significance of urokinase- type plasminogen activator, its inhibitors, and its receptor in ascites of patients with epithelial ovarian cancer.

Abstract

Strong correlations have been reported between expression of urokinase-type plasminogen activator (uPA) and poor prognosis in several human carcinomas. The clinical significance of secreted levels of uPA, its receptor (uPAR), and its inhibitors (PAI-1 and PAI-2) in the ascites of patients with epithelial ovarian cancer patients was investigated. uPA, uPAR, PAI-1, and PAI-2 were measured in the primary ascites of 36 patients with epithelial ovarian cancer by enzyme-linked immunosorbent assay, and normalized to protein content. The relationship between levels of these factors in ascites and clinicopathologic variables, survival, and disease free interval (DFI) was studied. Because high levels of macrophage colony stimulating factor (CSF-1) in ascites is a known poor prognostic indicator for ovarian cancer, the effect of CSF-1 on secretion of PAI-2 by ovarian cancer cells was also examined in vitro. High uPA levels per se did not correlate with either survival or DFI. However, the ratio of uPAR normalized for uPA content correlated inversely with FIGO stage and residual disease, with a significant association between high uPAR/uPA level and prolonged survival and DFI. High PAI-1 levels (> 0.120 ng/mg) proved to be a good prognostic factor, correlating with both prolonged DFI and residual disease < or = 5 cm among Stage 3 patients. Conversely, high levels of PAI-2 (> 0.061 ng/mg) indicated a poor prognosis in Stage 3 patients, as high PAI-2 levels were associated with shorter DFI and survival. CSF-1 stimulated the secretion of PAI-2 by 2.4-fold in Bix3 ovarian carcinoma cells. Multivariate analysis revealed that the two independent prognostic factors for DFI in Stage 3 patients were PAI-1 and PAI-2; Stage 3 patients with high secreted PAI-1 and low PAI-2 levels have a median DFI that was prolonged by 30 months relative to the rest of the group. Secreted uPAR/uPA appears to measure tumor burden and predicts prolonged DFI and survival, but was not found to be an independent prognostic factor on multivariate analysis. High levels of PAI-1 in ascites were independently associated with prolonged DFI among Stage 3 patients. Therefore, secreted uPAR and PAI-1 may modulate uPA activity and lead to improved outcome. This contrasts with the finding that secreted PAI-2 is an independent factor indicating poor prognosis, which may relate in part to the actions of CSF-1. This study emphasizes the importance of uPA, its receptor, and its inhibitors in patients with epithelial ovarian cancer.