Role of urokinase plasminogen activator and its receptor in metastasis and invasion of neuroblastoma.

Abstract Background/Purpose Urokinase plasminogen activator (uPA) is a serine proteinase that has been suggested to play an important role in tumor invasion and metastasis. It binds to a specific membrane receptor, uPA receptor (uPAR), and activates plasminogen to form plasmin, which participates in tissue degradation and proteolysis. Binding of uPA to its receptor accelerates the activation of uPA from pro-uPA, enhancing the activity of the uPA/uPAR cascade. Because of the high metastatic and invasive potential of neuroblastoma (NB) cells, the authors have analyzed in the current study, the concomitant of uPA and its receptor in NB. Methods The expression and distribution of uPA and uPAR were analyzed by immunostaining in 52 neuroblastoma tissues; at the same time we use the reverse transcriptase polymerase chain reaction (RT-PCR) for neuroendocrine protein gene products 9.5 (PGP 9.5) mRNA to detect small numbers of NB cells in the peripheral blood and bone marrow (BM) and study the relationship uPA and uPAR to the ability of invasion and metastasis of NB cells. To identify risk factors for disease progression, the authors performed a retrospective analysis of clinical (age, sex, and risk group) and tumor biologic markers (histology, MYCN , DNA ploidy, chromosome 1 p, PGP9.5, uPA, uPAR, and combined uPA and uPAR) in all patients. Survival curves were estimated using the Kaplan-Meier method. Univariate analysis was performed with the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression model. Results The results of immunohistochemistry showed that uPA and uPAR were localized mainly in the membrane and cytoplasm of tumor cells. The positive rate of uPA in the high-risk group (23 of 25, 92.0%) was remarkably higher than that in intermediate-risk group (8 of 17, 47.1%) and low-risk group (3 of 10, 30.0%), in UH (26 of 29, 89.7%) was higher than in FH (8 of 23, 34.8%), respectively, and statistical significance was remarkable both P P P P MYCN , and combined uPA and uPAR remained significant predictors for both OS and EFS ( P Conclusions This study showed that uPA and uPAR were overexpressed in high-risk and UH tumor of NB, and that overexpression of both factors was associated with the ability of invasion, metastasis, and prognosis of NB. The presence of high levels of combined uPA and uPAR may be a new prognostic marker that would allow us to identify patients with poorer prognosis who might benefit from more aggressive surgical and adjuvant treatment.