1: J Pediatr Surg. 2004 Oct;39(10):1512-9. 

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

Li P, Gao Y, Ji Z, Zhang X, Xu Q, Li G, Guo Z, Zheng B, Guo X.

Department of Pediatric Surgery, the Second Hospital of Xi'an Jiaotong
University, Xi'an, People's Republic of China.

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 < .01). Similar results were
obtained for uPAR. The positive rate of uPAR in the high-risk group (22 of 25,
88.0%) was substantially higher compared with that in intermediate-risk group (6
of 17, 35.3%) and low-risk group (2 of 10, 20.0%; P < .01). The positive rate of
uPAR in UH (24 of 29, 82.8%) was higher compared with that in FH (6 of 23,
26.1%), and statistical significance was remarkable (P < .01). PGP9.5 mRNA in
peripheral blood and BM was detected in 24 of 52 (45.2%) patients. The positive
rate of PGP 9.5 mRNA in peripheral blood and BM in the cases positive for uPA
(22 of 34, 64.7%) was markedly higher than that in the cases negative for uPA
(11.1%, 2 of 18), and statistical significance was remarkable (P < .01). There
was significant difference in the positive rate of PGP9.5 mRNA between the group
positive for uPAR (66.7%, 20 of 30) and the group negative for uPAR (18.2%, 4 of
22), and a larger difference was found between the group positive for both uPA
and uPAR (73.1%, 19 of 26) and the group negative for uPA or uPAR (19.2%, 5 of
26). The overall survival (OS) and event-free survival (EFS) rates at 5 years
for all patients were, respectively, 70% +/- 3% and 63% +/- 3% with a median
follow-up of 65 months (range 13 to 20). Among all the biologic and clinical
features analyzed, multivariate analysis using Cox proportional hazards
regression showed that age, MYCN, and combined uPA and uPAR remained significant
predictors for both OS and EFS (P < .01, respectively). Both EFS rate and OS
rate were significantly better for patients who positively expressed uPA and
uPAR than those who negatively expressed uPA or uPAR. 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.

PMID: 15486896 [PubMed - indexed for MEDLINE]


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