UROKINASE-TYPE PLASMINOGEN-ACTIVATOR IN EPITHELIAL OVARIAN-CANCER - APOOR PROGNOSTIC FACTOR, ASSOCIATED WITH ADVANCED-STAGE

Objective: Expression of urokinase-type plasminogen activator (uPA), a CSF-1 (macrophage colony stimulating factor) inducible gene, has been associated with invasion and metastatic properties, as well as with p oor prognosis in a variety of epithelial cancers. In ovarian cancer me tastases, co-expression of CSF-1 and CSF-1 receptor has been shown to be an independent poor prognostic factor for clinical outcome. Moreove r, CSF-1 stimulated invasion of ovarian cancer cells in vitro is media ted by uPA activity. Ovarian cancers contain a higher concentration of uPA and its receptor, uPAR, than benign ovarian tumors. Reports, howe ver, on the prognostic value of uPA content in ovarian cancer tissue e xtracts, which contain tumor epithelium, stroma, and infiltrating infl ammatory cells, have been conflicting. The objectives of this study ar e to determine: (1) the prognostic value of uPA or uPAR expression in ovarian cancer epithelium, (2) the level of uPA or uPAR staining in th e stromal cells, and (3) if there is an association between expression of uPA/uPAR and CSF-1/CSF-1 receptor in ovarian cancers. Methods: Imm unohistochemistry was used to study the primary and metastatic tissues from 131 epithelial ovarian carcinomas, which included all stages of disease. The intensity and extent of staining for uPA and uPAR in the tumor epithelium was scored. Kaplan-Meier curves of survival were comp ared with the log-rank test. The Cox regression model was used for mul tivariate analysis. The Chi square test was used to study the associat ion between uPA/uPAR immunohistochemical positivity and clinicopatholo gic parameters, as well as with CSF-1 and CSF-1 receptor expression. R esults: For the invasive cases, 66% of the primary tumors and 57% of t he metastases expressed uPA, while only 32% of the primary tumors and 23% of the metastases expressed uPAR. There was low level staining for uPA or uPAR in the stromal cells surrounding the tumor. Tumor cell ex pression of uPA in the invasive primary tumors was strongly predictive of a shorter overall survival; the median survival of 29 months for t he 76 patients whose primary tumors expressed uPA was extended to 53 m onths for the 40 patients whose primary tumors did not express uPA. Th e prognostic value of uPA expression was retained in the subgroup of p atients with residual disease greater than or equal to 2 cm, but not a mong patients with minimal or no residual disease. Urokinase expressio n was, however, significantly associated with advanced stage and older age, and was not an independent factor for survival on multivariate a nalysis. Expression of uPAR alone, or in combination with uPA, had no prognostic value in this study. Co-expression of uPA and uPAR was stro ngly associated with co-expression of CSF-1 and CSF-1 receptor. Conclu sions: The current study is the first to describe the prognostic signi ficance of uPA/uPAR expression localized to ovarian cancer epithelium. Two previous studies on ovarian cancer, as well as studies on breast, lung, gastric, colon, and cervical cancers, examined the prognostic v alue of uPA content in tissue extracts. We demonstrate that uPA expres sion in the primary tumor epithelium is a common finding which is sign ificantly predictive of a shorter overall survival, but is not an inde pendent factor, most likely due to its close association with advanced stage. On the other hand, ovarian cancer stromal staining for uPA was of a low level and was not a prominent feature. In this study, a sign ificant association was found between co-expression of uPA/uPAR and of CSF-1/CSF-1 receptor; thus components of the uPA system may act as a mediator of the invasive, poor prognosis phenotype conferred by CSF-1 in epithelial ovarian cancers.