Hypoxia and differentiation in human neuroblastoma cells

Abstract

The childhood tumour neuroblastoma is derived from immature cells of the sympathetic nervous system, which have become arrested at different maturation stages. Neuroblastoma is a malignancy with a high degree of heterogeneity, and there is a correlation between a poor differentiation status and a more aggressive phenotype. The MYCN gene is amplified in approximately 25% of neuroblastoma tumours and is correlated to an aggressive tumour phenotype. A role of MYCN in keeping these tumours at an immature stage has been suggested. However, we show that over-expression of MYCN in non-amplified neuroblastoma cells do not restrain their capacity to differentiate. Furthermore, in a panel of 28 neuroblastoma tumours and 27 cell lines, we do not see a correlation between the degree of MYCN expression and the expression of neuronal or neuroendocrine marker genes.



Previously hypoxia and/or nutrient deprivation has been suggested to induce a neuroendocrine lineage shift in neuroblastoma tumours. However, when growing neuroblastoma cell lines at hypoxia and/or low glucose conditions, we observe a down-regulation of both neuronal and chromaffin marker genes. Instead, genes normally expressed in early neural crest cells are induced. We therefore propose that hypoxia and/or glucose deficiency induce a dedifferentiation of neuroblastoma cells, thereby rendering them a more aggressive phenotype. In addition, when growing neuroblastoma cells at hypoxia and/or without glucose, we find that hypoxia protects from glucose-deprivation induced cell death. This further adds to the malignant potential of hypoxic neuroblastoma cells.



We have further investigated the hypoxia inducible transcription factors HIF-1a and HIF-2a in neuroblastoma cells and find that they have separate patterns of activation over time and in response to different oxygen levels.

• author: Nilsson, Helén
• supervisor: Sven Påhlman
• opponent: Professor Fandrey, Joachim, University of Duisburg-Essen, Germany
• organization: Department of Translational Medicine
• publishing date: 2005
• type: Thesis
• publication status: published
• subject: Cancer and Oncology
• keywords: ontogeny, embryology (human), Utvecklingsbiologi, teratologi, embryologi (människa), teratology, cytogenetik, Development biology, cytogenetics, Genetik, Genetics, Medicin (människa och djur), HIF, Medicine (human and vertebrates), MYCN, Hypoxia, differentiation, Neuroblastoma
• in: Lund University Faculty of Medicine Doctoral Dissertation Series
• volume: 2005:54
• pages: 112 pages
• defense location: Main lecture hall, Pathology building, Entrance 78, floor 2, University Hospital MAS, Malmö
• defense date: 2005-06-10 09:15:00
• ISSN: 1652-8220
• ISBN: 91-85439-59-2
• language: English
• LU publication?: yes
• additional info: . 2004. Neuroblastoma cells with overexpressed MYCN retain their capacity to undergo neuronal differentiation Lab. Invest., vol 84 pp 406-417.; . 2002. Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype PNAS, vol 99 pp 7021-7026.; . 2005. HIF-2alpha expression in human fetal paraganglia and neuroblastoma: relation to sympathetic differentiation, glucose deficiency, and hypoxia. Exp. Cell Res., vol 303 pp 447-456.; . . Hypoxia rescues neuroblastoma cells from glucose deficiency-induced cell death. (manuscript); . . Gene regulation in hypoxic neuroblastoma cells - different roles of HIF-1alpha and HIF-2alpha. (manuscript) The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Molecular Medicine (013031200)
• id: 9adca2f5-03fa-46bb-a08c-f65df47786cd (old id 545097)
• date added to LUP: 2016-04-01 16:48:57
• date last changed: 2019-11-19 13:49:07