Predictive Value of the Differential Expression of the Urokinase Plasminogen Activation Axis in Radical Prostatectomy Patients

Background: The urokinase plasminogen axis is composed of urokinase plasminogen activator (uPA), its receptor (uPAR), and its inhibitors (PAI-1 and PAI-2). This axis is involved in cell proliferation, angiogenesis, extracellular matrix degradation, invasion, and metastases. Objective: To assess the relationship of the uPA axis with pathologic features and outcomes in prostate cancer. Design, setting, and participants: Retrospective study of 230 consecutive patients treated with radical prostatectomy for clinically localized disease. Interventions: None. Measurements: Immunohistochemical staining for uPA, uPAR, and PAI-1 were carried out on serial archival tissue microarray specimens. These markers were histologically categorized as normal or overexpressed. Disease recurrence was classified as aggressive if metastases were present, if postrecurrence prostate-specific antigen (PSA) doubling time was <10 mo, or if the patients failed to respond to salvage local radiation therapy. Results and limitations: The median follow-up was 63 mo. The combined expression of uPA and PAI-1 was associated with extraprostatic extension (p = 0.01) and seminal vesicle invasion (p = 0.008). On multivariable analysis, the combined uPA/PAI-1 expression was associated with overall (risk ratio [RR]: 2.3; 95% confidence interval [CI]: 1.1-4.8; p = 0.02) and aggressive disease recurrence (RR: 9.4; 95% CI: 3.5-25; p < 0.0001) but not with nonaggressive disease recurrence. Expression of uPAR was not associated with any of the outcomes. The study is limited by its retrospective nature and lack of long-term follow-up. Conclusions: Overexpression of both uPA and PAI-1 is associated with adverse pathologic features and higher risk of overall and aggressive disease recurrence in men treated with radical prostatectomy for clinically localized prostate cancer. After validation, these markers may be useful in selecting patients most likely to benefit from adjuvant therapy. These markers should also be considered for addition into postoperative prediction tools.