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

Research output: Contribution to journalArticle

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.

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Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
  • Cancer and Oncology
  • Cell and Molecular Biology

Keywords

  • hypoxia, HIF-1, differentiation, tumor stroma, sympathetic nervous, system
Original languageEnglish
Pages (from-to)16805-16810
JournalProceedings of the National Academy of Sciences
Volume106
Issue number39
Publication statusPublished - 2009
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

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)