Role of Phox2B in neuroblastoma development

Abstract

Neuroblastoma (NB) a common childhood malignant tumor of the sympathetic nervous system presents as a heterogeneous group of tumors ranging from tumors comprising of undifferentiated neuroblasts to those largely consisting of fully differentiated neurons. We have used MYCN transgenic mice‐ mice with targeted expression of the oncogene MYCN in neural crest cells‐ as a model system to investigate the cellular basis for NB development. These mice develop overt neuroblastomas preceded by a pre‐neoplastic stage characterized by development of hyperplastic lesions in the post‐natal sympathetic ganglia. Immunostaining analysis of these lesions revealed extensive proliferation and absence of staining with sympathetic differentiation markers, indicating their undifferentiated state. A majority of the hyperplastic cells as well as majority of cells in all primary tumors examined showed strong staining for Phox2B, a marker of sympathetic neural progenitors. Recently, we observed that retinoic‐acid induced differentiation of human NB cell lines is accompanied by a marked down‐regulation of Phox2B suggesting that Phox2B may be important for maintenance of the neuroblasts characterizing NB tumors. Also, Phox2B down‐regulation in the human NB cell line SK‐N‐AS results in decreased survival of cells. Given together, these data suggest that Phox2B may function as a lineage‐survival oncogene in NB development.NCI