The role of Notch signaling pathway in neuronal differentiation of neuroblastoma and prognosis of patients with neuroblastoma
Other Title
Notch 訊息傳遞路徑對於神經母細胞瘤細胞分化的機制及其與病人預後關係之研究
Date Issued
2010
Date
2010
Author(s)
Abstract
Neuroblastoma (NB) is a childhood tumor derived from sympathoadrenal lineage of the neural crest progenitor cells. It is one of the most common pediatric cancers with an incidence of 8.0 per million per year, and 96% of cases occur before the age of 10 years. The disease is remarkable for its broad spectrum of clinical manifestations. The heterogeneity of NB tumors is largely due to the diverse biological characteristics that link to the prognosis of the patients. The differentiation status of tumor histology is also an important prognostic factor in NB, and differentiating therapy has been proven to improve the outcomes of NB patients.
Notch signaling has been implicated to play a critical role in the tumorigenesis of neuroblastoma (NB), and can modulate calreticulin (CRT) expression that strongly correlates with tumor differentiation and favorable prognosis of NB. We thus sought to determine how Notch regulates CRT expression and affects NB tumor behavior, and the prognostic role of Notch signaling in patients with NB.
We examined Notch1 protein expression in 85 NB tumors by immunohistochemical staining and correlated its expression levels with the clinicopathologic/biologic characters of the patients. The molecular mechanism underlying the Notch-dependent regulation of neuronal differentiation was determined by using cultured NB cells. The Notch-dependent regulation of CRT expression in cultured NB cells was analyzed by confocal microscopy and Western blotting. The effects of attenuated Notch signaling on NB tumor growth were examined by a xenograft mouse model of NB.
NB tumors with elevated Notch1 protein expression were strongly correlated with advanced tumor stages, MYCN amplification, an undifferentiated histology, as well as a low CRT expression level. Using survival analysis, we demonstrated that patients with positive Notch1 expression on NB tumors exhibit a five-year overall survival rate of 28.5 % comparing to 85 % (P < 0.001, log-rank test) among those with negative Notch1 expression. Most importantly, the opposing effect between Notch1 and CRT could reciprocally affect NB patient survival. Consistently, high levels of Notch1 protein independently predicted poor prognosis of NB patients in multivariate analysis. We further demonstrated that CRT is essential for the neuronal differentiation of NB cells elicited by inhibition of Notch signaling. This effect was mediated by a JNK-dependent pathway. To substantiate the role of Notch signaling in the progression of NB, the administration of a γ-secretase inhibitor (GSI) into a xenograft mouse model of NB resulted in a significant suppression in NB tumor growth, concomitant with a prominent differentiation in xenograft tumors.
Our findings provide the evidence for the first time that a JNK-CRT-dependent pathway is essential for the neuronal differentiation elicited by Notch signaling blockade and that Notch1 and CRT can synergistically predict the clinical outcomes of NB patients. The present data suggest that Notch signaling could be a therapeutic target for NB and that GSI could be the basis for the development of novel drugs for the treatment of NB.
Subjects
neuroblastoma
Notch signaling pathway
differentiation therapy
SDGs
Type
dissertation
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