title: HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells.
abstract: High hypoxia-inducible factor-2alpha (HIF-2alpha) protein levels predict poor outcome in neuroblastoma, and hypoxia dedifferentiates cultured neuroblastoma cells toward a neural crest-like phenotype. Here, we identify HIF-2alpha as a marker of normoxic neural crest-like neuroblastoma tumor-initiating/stem cells (TICs) isolated from patient bone marrows. Knockdown of HIF-2alpha 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-2alpha-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-2alpha maintains an undifferentiated state of neuroblastoma TICs. Because low differentiation is associated with poor outcome and angiogenesis is crucial for tumor growth, HIF-2alpha is an attractive target for neuroblastoma therapy.
authors.affiliation: Department of Laboratory Medicine, Center for Molecular Pathology, CREATE Health, University Hospital MAS, Lund University, Malmö, Sweden.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pietras
authors.forename: Loen M
authors.initials: LM
authors.lastname: Hansford
authors.forename: A Sofie
authors.initials: AS
authors.lastname: Johnsson
authors.forename: Esther
authors.initials: E
authors.lastname: Bridges
authors.forename: Jonas
authors.initials: J
authors.lastname: Sjölund
authors.forename: David
authors.initials: D
authors.lastname: Gisselsson
authors.forename: Matilda
authors.initials: M
authors.lastname: Rehn
authors.forename: Siv
authors.initials: S
authors.lastname: Beckman
authors.forename: Rosa
authors.initials: R
authors.lastname: Noguera
authors.forename: Samuel
authors.initials: S
authors.lastname: Navarro
authors.forename: Jörg
authors.initials: J
authors.lastname: Cammenga
authors.forename: Erik
authors.initials: E
authors.lastname: Fredlund
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
authors.forename: Sven
authors.initials: S
authors.lastname: Påhlman
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009432:Neural Crest / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism*; D042442:Vascular Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D042442:Vascular Endothelial Growth Factors; D000099162:Endothelial PAS Domain-Containing Protein 1