Background: The urokinase plasminogen activator receptor (uPAR) moderates cell adhesion, migration and proliferation and has been found to be up regulated in a variety of malignancies. Several studies inversely associate uPAR expression in both neoplastic and tumor-associated stromal cells with survival in colorectal, breast and renal carcinoma. In the present study the expression pattern of uPAR and its association with survival was determined in a large cohort of pancreatic adenocarcinoma patients.
Methodology: A tissue microarray (TMA) was constructed by punching representative triplicate 2.0 mm cores from formalin-fixed and paraffin-embedded tissue blocks. The tissues were derived from 137 patients with pancreatic adenocarcinoma who underwent surgery with curative intent between 2001 and 2012. Immunohistochemical staining for uPAR, alpha smooth muscle actin and vimentin was conducted to identify uPAR positive cells, myofibroblasts and mesenchymal cells, respectively. uPAR-positive cells were classified as neoplastic or stromal cells. Furthermore, staining was dichotomized as low (<50% cells moderate/strong expression) or high (>50% cells moderate/strong expression). Kaplan-Meier curves and uni- and multivariate Cox regression analyses were used to compare uPAR expression with overall survival and disease free survival.
Findings: uPAR expression could be quantified in 89% (n=122) of the pancreatic adenocarcinomas. 66% of the cases (n=81) expressed an elevation of uPAR in neoplastic cells and 82% (n=100) in tumor-associated stromal cells (including myofibroblasts and mesenchymal cells). Tumor-associated stromal cell expression was correlated with neoplastic uPAR expression (p<0.001). 62% of the patients (n=75) had an elevated uPAR expression in neoplastic cells as well as stromal cells. Multivariate analyses showed a significant inverse relationship between uPAR expression in neoplastic cells and in both neoplastic and tumor-associated cells with overall survival and disease free survival. uPAR expression in stromal cells lost its significance in multivariate analyses.
Conclusion: uPAR is a potential biomarker capable of identifying high-risk pancreatic adenocarcinomas.