HIF-2 alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells
(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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- author
- organization
- publishing date
- 2009
- type
- 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 Academy of Sciences
- external identifiers
-
- wos:000270305800048
- scopus:70349753257
- ISSN
- 1091-6490
- DOI
- 10.1073/pnas.0904606106
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Molecular Medicine (013031200), Division of Clinical Genetics (013022003), Stem Cell Center (013041110)
- id
- 4a19041f-4fbd-439c-8540-d6c443572417 (old id 1488484)
- date added to LUP
- 2016-04-01 11:41:30
- date last changed
- 2022-01-26 08:50:26
@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}}, keywords = {{hypoxia; HIF-1; differentiation; tumor stroma; sympathetic nervous; system}}, language = {{eng}}, number = {{39}}, pages = {{16805--16810}}, publisher = {{National Academy of 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}}, doi = {{10.1073/pnas.0904606106}}, volume = {{106}}, year = {{2009}}, }