PMID- 19805377
OWN - NLM
STAT- MEDLINE
DCOM- 20091228
LR  - 20211020
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 106
IP  - 39
DP  - 2009 Sep 29
TI  - HIF-2alpha maintains an undifferentiated state in neural crest-like human 
      neuroblastoma tumor-initiating cells.
PG  - 16805-10
LID - 10.1073/pnas.0904606106 [doi]
AB  - 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.
FAU - Pietras, Alexander
AU  - Pietras A
AD  - Department of Laboratory Medicine, Center for Molecular Pathology, CREATE Health, 
      University Hospital MAS, Lund University, Malmo, Sweden.
FAU - Hansford, Loen M
AU  - Hansford LM
FAU - Johnsson, A Sofie
AU  - Johnsson AS
FAU - Bridges, Esther
AU  - Bridges E
FAU - Sjolund, Jonas
AU  - Sjolund J
FAU - Gisselsson, David
AU  - Gisselsson D
FAU - Rehn, Matilda
AU  - Rehn M
FAU - Beckman, Siv
AU  - Beckman S
FAU - Noguera, Rosa
AU  - Noguera R
FAU - Navarro, Samuel
AU  - Navarro S
FAU - Cammenga, Jorg
AU  - Cammenga J
FAU - Fredlund, Erik
AU  - Fredlund E
FAU - Kaplan, David R
AU  - Kaplan DR
FAU - Pahlman, Sven
AU  - Pahlman S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090916
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - 1B37H0967P (endothelial PAS domain-containing protein 1)
SB  - IM
MH  - Animals
MH  - Basic Helix-Loop-Helix Transcription Factors/genetics/*metabolism
MH  - *Cell Differentiation
MH  - Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Down-Regulation
MH  - Female
MH  - Humans
MH  - Mice
MH  - Mice, Nude
MH  - Neural Crest/*metabolism
MH  - Neuroblastoma/*metabolism
MH  - Vascular Endothelial Growth Factors/genetics/metabolism
PMC - PMC2745331
COIS- The authors declare no conflict of interest.
EDAT- 2009/10/07 06:00
MHDA- 2009/12/29 06:00
PMCR- 2009/09/16
CRDT- 2009/10/07 06:00
PHST- 2009/10/07 06:00 [entrez]
PHST- 2009/10/07 06:00 [pubmed]
PHST- 2009/12/29 06:00 [medline]
PHST- 2009/09/16 00:00 [pmc-release]
AID - 0904606106 [pii]
AID - 9651 [pii]
AID - 10.1073/pnas.0904606106 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2009 Sep 29;106(39):16805-10. doi: 
      10.1073/pnas.0904606106. Epub 2009 Sep 16.