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

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

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)16805-16810
JournalProceedings of the National Academy of Sciences
Issue number39
Publication statusPublished - 2009

Bibliographical 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)

Subject classification (UKÄ)

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

Free keywords

  • hypoxia
  • HIF-1
  • differentiation
  • tumor stroma
  • sympathetic nervous
  • system


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