Enhanced expression of urokinase plasminogen activator and its receptor in pancreatic carcinoma

Abstract

Urokinase plasminogen activator (uPA) is a serine proteinase that has been suggested to play an important role in cancer invasion and metastasis. It binds to a specific membrane receptor denominated uPA receptor (uPAR). uPA activates plasminogen to form plasmin, which participates in tissue degradation and proteolysis. Binding of uPA to its receptor accelerates UPA's own activation from pro-uPA, enhancing the activity of the uPA/uPAR cascade. Using immunohistochemistry and Northern blot analysis, we analysed the role of uPA and uPAR in 30 human pancreatic cancers. Immunohistochemical analysis demonstrated moderate to strong immunostaining of both factors in most pancreatic cancers. Cancer lesions with signs of invasion exhibited the strongest immunohistochemical signals for both factors. In addition, in desmoplastic areas adjacent to the cancer cells, moderate uPA and uPAR immunoreactivity was detectable. Northern blot analysis revealed a sixfold and a fourfold increase in uPA and uPAR mRNA levels in pancreatic cancer, respectively, in comparison with normal controls (P<0.01). Correlation of the Northern blot data with the clinical parameters of the patients indicated that patients with concomitant overexpression of uPA and uPAR had a shorter post-operative survival (median 9 months; mean+/-s.d. 10.2+/-3.6 months) than patients in whom only one or none of these factors were overexpressed (median 18 months; mean+/-s.d. 20.3+/-8.7 months) (P<0.002). Our data suggest that uPA and uPAR may serve as prognostic markers in human pancreatic cancer and that the marked overexpression of both factors may create an environment that enables pancreatic cancer cells to invade surrounding tissues.