Background: The urokinase plasminogen activator (uPA) system has been implicated in progression and poor prognosis in epithelial ovarian cancer (EOC) patients. The present study investigated the distribution of uPA and its receptor (uPAR) in EOC cell lines, primary and metastatic tumors, and the relationship between uPA/uPAR and matrix metalloproteinase (MMP) expression using immunohistochemistry. We also studied the association between uPA/uPAR expression and clinical and pathological parameters including disease progression free survival (PFS).
Methods: The expression of uPA/uPAR was examined on paraffin-embedded tissue sections from primary EOC (n=100), and matched metastatic lesions (n=30) of untreated patients, normal ovarian tissues (n=20) as well as 8 primary and metastatic EOC cell lines by immunohistochemistry. Co-immunolabeling of uPA and MMP-1, -2, -9 or MT1-MMP was examined using confocal microscopy.
Results: The expression of uPA/uPAR was found in most primary (92% and 88% positive, respectively), metastatic ovarian tumors (93% and 90% positive, respectively), and all of examined EOC cell lines. The majority of specimens showed moderate to strong immunostaining of tumor and stromal cells; for primary specimens, this was significantly associated with tumor stage, grade and time to relapse (P<0.01). Overexpression of uPA/uPAR was found to be associated with an unfavorable prognosis with significantly reduced median disease PFS of 16 vs. 33 months for uPA (P<0.001), and 15 vs. 28 months for uPAR (P<0.001). Co-localization of uPA with MMP-1, -2, -9 or MT1-MMP was also seen in primary tumors and metastatic lesions.
Conclusions: The expression of uPA/uPAR was associated with EOC progression. uPA/uPAR are useful markers for EOC prognosis and could be promising therapeutic targets for treating incurable, recurrent EOC.