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

Author:
  • Alexander Pietras
  • Loen M. Hansford
  • Sofie Mohlin
  • Esther Bridges Baxter
  • Jonas Sjölund
  • David Gisselsson Nord
  • Matilda Rehn
  • Siv Beckman
  • Rosa Noguera
  • Samuel Navarro
  • Jörg Cammenga
  • Erik Fredlund
  • David R. Kaplan
  • Sven Påhlman
Publishing year: 2009
Language: English
Pages: 16805-16810
Publication/Series: Proceedings of the National Academy of Sciences
Volume: 106
Issue: 39
Document type: Journal article
Publisher: National Acad Sciences

Abstract english

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.

Keywords

  • Medical Genetics
  • Cancer and Oncology
  • Cell and Molecular Biology
  • hypoxia
  • HIF-1
  • differentiation
  • tumor stroma
  • sympathetic nervous
  • system

Other

Published
  • CREATE Health
  • Brain Tumor Biology
  • ISSN: 1091-6490
Sven Påhlman
E-mail: sven.pahlman [at] med.lu.se

Professor

Division of Translational Cancer Research

+46 46 222 64 21

MV406 312K1

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