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|Title||Hypoxia and differentiation in human neuroblastoma cells|
|Full-text||Available as PDF|
|Defence place||Main lecture hall, Pathology building, Entrance 78, floor 2, University Hospital MAS, Malmö|
|Opponent||Professor Joachim Fandrey|
|Publication/Series||Lund University Faculty of Medicine Doctoral Dissertation Series|
|Publisher||Lund University, Faculty of Medicine|
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.
Medicine and Health Sciences
Biology and Life Sciences
|Keywords||embryology (human), ontogeny, Utvecklingsbiologi, teratologi, embryologi (människa), teratology, cytogenetik, Development biology, cytogenetics, Genetik, Genetics, Medicin (människa och djur), HIF, Medicine (human and vertebrates), MYCN, Hypoxia, differentiation, Neuroblastoma|
. 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)