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Differentiation in Neuroblastoma: Diffusion-Limited Hypoxia Induces Neuro-Endocrine Secretory Protein 55 and Other Markers of a Chromaffin Phenotype

Hedborg, F; Fischer-Colbrie, R; Ostlin, N; Sandstedt, B; Tran, MGB; Maxwell, PH; (2010) Differentiation in Neuroblastoma: Diffusion-Limited Hypoxia Induces Neuro-Endocrine Secretory Protein 55 and Other Markers of a Chromaffin Phenotype. PLOS ONE , 5 (9) , Article e12825. 10.1371/journal.pone.0012825. Green and gold open access

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Abstract

Background: Neuroblastoma 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 Findings: Immunohistochemical 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 HIF2 alpha. Anaerobic culture of five neuroblastoma cell lines resulted in an 18.9-fold mean up-regulation of NESP55.Conclusions/Significance: The 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.

Type:Article
Title:Differentiation in Neuroblastoma: Diffusion-Limited Hypoxia Induces Neuro-Endocrine Secretory Protein 55 and Other Markers of a Chromaffin Phenotype
Open access status:An open access publication. A version is also available from UCL Discovery.
DOI:10.1371/journal.pone.0012825
Publisher version:http://dx.doi.org/10.1371/journal.pone.0012825
Language:English
Additional information:© 2010 Hedborg et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The project was supported by grants from Lion's Cancer Fund of the Uppsala-Orebro Region (http://www.lcff.se/), and by governmental and local funding via the regional health care organisation of Uppsala County (http://www.medfarm.uu.se/intranet/ALF/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords:IGF2 EXPRESSION, GENE-EXPRESSION, ADRENAL-MEDULLA, NERVOUS-SYSTEM, CELLS, HIF-2-ALPHA, HIF-1-ALPHA, NESP55, GROWTH, TUMORS
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)

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