Abstract
BackgroundNeuroblastoma is a childhood malignancy of sympathetic embryonal origin. A high potential for differentiation is a hallmark of neuroblastoma cells. We have previously presented data to suggest that in situ differentiation in tumors frequently proceeds along the chromaffin lineage and that decreased oxygen (hypoxia) plays a role in this. Here we explore the utility of Neuro-Endocrine Secretory Protein 55 (NESP55), a novel member of the chromogranin family, as a marker for this process.Methodology/Principal FindingsImmunohistochemical analyses and in situ hybridizations were performed on human fetal tissues, mouse xenografts of human neuroblastoma cell lines, and on specimens of human neuroblastoma/ganglioneuroma. Effects of anaerobic exposure on gene expression by cultured neuroblastoma cells was analyzed with quantitative real-time PCR. Fetal sympathetic nervous system expression of NESP55 was shown to be specific for chromaffin cell types. In experimental and clinical neuroblastoma NESP55 immunoreactivity was specific for regions of chronic hypoxia. NESP55 expression also correlated strikingly with morphological evidence of differentiation and with other chromaffin-specific patterns of gene expression, including IGF2 and HIF2α. Anaerobic culture of five neuroblastoma cell lines resulted in an 18.9-fold mean up-regulation of NESP55.Conclusions/SignificanceThe data confirms that chronic tumor hypoxia is a key microenvironmental factor for neuroblastoma cell differentiation, causing induction of chromaffin features and NESP55 provides a reliable marker for this neuronal to neuroendocrine transition. The hypoxia-induced phenotype is the predominant form of differentiation in stroma-poor tumors, while in stroma-rich tumors the chromaffin phenotype coexists with ganglion cell-like differentiation. The findings provide new insights into the biological diversity which is a striking feature of this group of tumors.
Highlights
Neuroblastoma is a childhood malignancy of sympathetic embryonal origin
We previously showed that certain characteristics of sympathetic neuroendocrine cells [8] are frequent in neuroblastoma [9,10] Interestingly these occur centrally within tumor nodules and in perinecrotic areas, representing regions of chronic tumor hypoxia and in vitro these neuroendocrine features are highly induced by hypoxia [11,12]
When testing at a four-fold increased anti-Neuro-Endocrine Secretory Protein 55 (NESP55) antibody concentration a weak and general cytoplasmic immunoreactivity was evident at this stage of ganglion cell differentiation (Fig. 1: G)
Summary
The aim of this study was to explore the chromaffin marker qualities of NESP55 during human development and whether its presence in neuroblastoma may be a consequence of tumor hypoxia
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