Notch1 expression predicts an unfavorable prognosis and serves as a therapeutic target of patients with neuroblastoma (original) (raw)
Purpose: 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. Experimental Design: The Notch-dependent regulation of CRT expression in cultured NB cells was analyzed by confocal microscopy and Western blotting. Notch1 protein expression in 85 NB tumors was examined by immunohistochemistry and correlated with the clinicopathologic/biological characters of NB patients. The progression of NB tumors in response to attenuated Notch signaling was examined by using a xenograft mouse model. Results: We showed that CRT is essential for the neuronal differentiation of NB cells elicited by inhibition of Notch signaling. This effect was mediated by a c-Jun-NH 2-kinase-dependent pathway. Furthermore, 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. Most importantly, the opposing effect between Notch1 and CRT could reciprocally affect the survival of NB patients. The administration of a γ-secretase inhibitor into a xenograft mouse model of NB significantly suppressed the tumor progression. Conclusions: Our findings provide the first evidence that a c-Jun-NH 2-kinase-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. Clin Cancer Res; 16(17); 4411-20. ©2010 AACR. 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; more than 90% of NB patients are diagnosed as having the disease before the age of 10 years (1). Most children who are older than 1 year at the time of diagnosis exhibit advanced or metastatic disease, and their overall prognosis remains poor (2). The disease is remarkable for its broad spectrum of clinical manifestations. The clinical behaviors of NB can be categorized into three distinct patterns: (a) life-threatening progression, (b) maturation to ganglioneuroblastoma (GNB) or ganglioneuroma, and (c) spontaneous regression (3). The heterogeneity of NB tumors is largely due to the diverse biological characteristics that link to the
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