HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells.
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.
Pietras
Alexander
A
Department of Laboratory Medicine, Center for Molecular Pathology, CREATE Health, University Hospital MAS, Lund University, Malmö, Sweden.
Hansford
Loen M
LM
Johnsson
A Sofie
AS
Bridges
Esther
E
Sjölund
Jonas
J
Gisselsson
David
D
Rehn
Matilda
M
Beckman
Siv
S
Noguera
Rosa
R
Navarro
Samuel
S
Cammenga
Jörg
J
Fredlund
Erik
E
Kaplan
David R
DR
Påhlman
Sven
S
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
D051792:Basic Helix-Loop-Helix Proteins; D042442:Vascular Endothelial Growth Factors; D000099162:Endothelial PAS Domain-Containing Protein 1