Urokinase (upa) activity, a mediator of the invasive phenotype conferred by csf-1 in epithelial ovarian cancer

Background: Expression of uPA, a CSF-1 (macrophage colony stimulating factor) inducible gene, has been associated with invasion and poor prognosis in several epithelial cancers. In ovarian cancers, elevated CSF-1 levels in ascites and serum portend a poor prognosis, as does co-expression of CSF-1 and CSF-1 receptor in ovarian cancer métastases. CSF-1 also increases the invasive capacity of ovarian cancer cells through the actions of uPA. Methods: Immunohistochemistry (MC) was used to study the primary and metastatic tissues from 131 epithelial ovarian cancer cases for uPA, uPAR, PAI-1, and PAI-2 expression. Statistical analysis was performed using the SAS statistical package. The effect of CSF-1 on PAI-1, PAI-2, and uPA expression in ovarian cancer cells was examined by enzyme-linked immunosorbent assay of the conditioned medium, and IHC of the cells. Results: CSF-1 increases the secretion of uPA, PAI-1, PAI-2, as well as membrane associated uPA and cellular PAI-1, while decreasing cellular PAI-2 expression. In invasive cancers of all stages, uPA expression (primary tumors) in vivo is associated with advanced stage and is prognostic of poor overall survival. Among Stages HI and IV cases, elevated levels of PAI-1 (primary tumors), and low levels of PAI-2 (métastases), are independent poor prognostic factors for survival, and are not significantly associated with standard clinical parameters. Among the primary tumors, CSF-1 expression is correlated with PAI-1 (positively), and PAI-2 (negatively) in vivo. Moreover, co-expression of uPA/uPAR is strongly associated with co-expression of CSF-l/CSF-1 receptor. Conclusions: CSF-1 does not encode for a protease capable of enhancing invasiveness or metastasis. These data support uPA (along with those factors which modulate its activity) as an important mediator of the invasive, poor prognosis phenotype conferred by CSF-1 in epithelial ovarian cancers. CSF-1 may also underlie our previous findings that elevated levels of PAI-2 in ovarian cancer ascites is a poor prognostic factor. We are the first to report on the prognostic significance of uPA (and its modulators) localized to ovarian cancer epithelium. While the reports on uPA and PAI-1 in ovarian cancer extracts have been conflicting, our findings are largely in line with those seen in nongynecologic cancer tissue extracts.