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HIF-2 alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells

Pietras, Alexander LU ; Hansford, Loen M.; Mohlin, Sofie LU ; Bridges Baxter, Esther LU ; Sjölund, Jonas LU ; Gisselsson Nord, David LU ; Rehn, Matilda LU ; Beckman, Siv LU ; Noguera, Rosa and Navarro, Samuel, et al. (2009) In Proceedings of the National Academy of Sciences 106(39). p.16805-16810
Abstract
High hypoxia-inducible factor-2 alpha (HIF-2 alpha) protein levels predict poor outcome in neuroblastoma, and hypoxia dedifferentiates cultured neuroblastoma cells toward a neural crest-like phenotype. Here, we identify HIF-2 alpha as a marker of normoxic neural crest-like neuroblastoma tumor-initiating/stem cells (TICs) isolated from patient bone marrows. Knockdown of HIF-2 alpha reduced VEGF expression and induced partial sympathetic neuronal differentiation when these TICs were grown in vitro under stem cell-promoting conditions. Xenograft tumors of HIF-2 alpha-silenced cells were widely necrotic, poorly vascularized, and resembled the bulk of tumor cells in clinical neuroblastomas by expressing additional sympathetic neuronal markers,... (More)
High hypoxia-inducible factor-2 alpha (HIF-2 alpha) protein levels predict poor outcome in neuroblastoma, and hypoxia dedifferentiates cultured neuroblastoma cells toward a neural crest-like phenotype. Here, we identify HIF-2 alpha as a marker of normoxic neural crest-like neuroblastoma tumor-initiating/stem cells (TICs) isolated from patient bone marrows. Knockdown of HIF-2 alpha reduced VEGF expression and induced partial sympathetic neuronal differentiation when these TICs were grown in vitro under stem cell-promoting conditions. Xenograft tumors of HIF-2 alpha-silenced cells were widely necrotic, poorly vascularized, and resembled the bulk of tumor cells in clinical neuroblastomas by expressing additional sympathetic neuronal markers, whereas control tumors were immature, well-vascularized, and stroma-rich. Thus, HIF-2 alpha maintains an undifferentiated state of neuroblastoma TICs. Because low differentiation is associated with poor outcome and angiogenesis is crucial for tumor growth, HIF-2 alpha is an attractive target for neuroblastoma therapy. (Less)
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Contribution to journal
publication status
published
subject
keywords
hypoxia, HIF-1, differentiation, tumor stroma, sympathetic nervous, system
in
Proceedings of the National Academy of Sciences
volume
106
issue
39
pages
16805 - 16810
publisher
National Acad Sciences
external identifiers
  • wos:000270305800048
  • scopus:70349753257
ISSN
1091-6490
DOI
10.1073/pnas.0904606106
project
CREATE Health
language
English
LU publication?
yes
id
4a19041f-4fbd-439c-8540-d6c443572417 (old id 1488484)
date added to LUP
2009-10-22 12:05:39
date last changed
2017-11-19 03:26:44
@article{4a19041f-4fbd-439c-8540-d6c443572417,
  abstract     = {High hypoxia-inducible factor-2 alpha (HIF-2 alpha) protein levels predict poor outcome in neuroblastoma, and hypoxia dedifferentiates cultured neuroblastoma cells toward a neural crest-like phenotype. Here, we identify HIF-2 alpha as a marker of normoxic neural crest-like neuroblastoma tumor-initiating/stem cells (TICs) isolated from patient bone marrows. Knockdown of HIF-2 alpha reduced VEGF expression and induced partial sympathetic neuronal differentiation when these TICs were grown in vitro under stem cell-promoting conditions. Xenograft tumors of HIF-2 alpha-silenced cells were widely necrotic, poorly vascularized, and resembled the bulk of tumor cells in clinical neuroblastomas by expressing additional sympathetic neuronal markers, whereas control tumors were immature, well-vascularized, and stroma-rich. Thus, HIF-2 alpha maintains an undifferentiated state of neuroblastoma TICs. Because low differentiation is associated with poor outcome and angiogenesis is crucial for tumor growth, HIF-2 alpha is an attractive target for neuroblastoma therapy.},
  author       = {Pietras, Alexander and Hansford, Loen M. and Mohlin, Sofie and Bridges Baxter, Esther and Sjölund, Jonas and Gisselsson Nord, David and Rehn, Matilda and Beckman, Siv and Noguera, Rosa and Navarro, Samuel and Cammenga, Jörg and Fredlund, Erik and Kaplan, David R. and Påhlman, Sven},
  issn         = {1091-6490},
  keyword      = {hypoxia,HIF-1,differentiation,tumor stroma,sympathetic nervous,system},
  language     = {eng},
  number       = {39},
  pages        = {16805--16810},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {HIF-2 alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells},
  url          = {http://dx.doi.org/10.1073/pnas.0904606106},
  volume       = {106},
  year         = {2009},
}