The Plasminogen Activation System in Human Endometrium and Endometrial Cancer; Function, Tissue Localization and Prognostic Importance

Sammanfattning: The release of urokinase plasminogen activator (uPA) from endometrial stromal cells decreased after progesterone stimulation, due to upregulation of PA inhibitor 1 (PAI-1) and uPA receptor (uPAR). Subsequently, the uPA:PAI-1 complex was internalized and degraded via uPAR. Predecidual cells in the late secretory phase expressed PAI-1 and uPAR, supporting a specific role for predecidual cells in the down-regulation of uPA. The tissue content of uPA protein and mRNA did not vary over the menstrual cycle. The tissue distribution of uPA and uPAR mRNAs and proteins indicated that the proteins bind in a paracrine way to epithelial cells. All factors were strongly expressed in the menstrual phase, suggesting a function in extracellular matrix (ECM) degradation and blood clot lysis during menstruation. Malignant endometrial tissue had a higher content of uPA protein than normal tissue. Also, the uPA content gradually increased from simple hyperplasia to poorly differentiated cancer. In contrast, the content of tPA mRNA and protein gradually decreased from simple hyperplasia to poorly differentiated cancer. The tumor tissue content of PAI-2 was a marker of poor postoperative prognosis in patients with endometrial cancer (HR=3.0; 95% CI 1.3-7.1), whereas the content of uPAR was not associated with survival. The combination of high PAI-1 and high PAI-2 selected a group of patients with 50% cumulated progression rate. A prognostic index based on “traditional” factors and this combination may improve assessment of the risk for individual patients with stage I-II endometrial cancer.