PMID- 19770585
OWN - NLM
STAT- MEDLINE
DCOM- 20091221
LR  - 20220409
IS  - 1551-4005 (Electronic)
IS  - 1538-4101 (Print)
IS  - 1551-4005 (Linking)
VI  - 8
IP  - 20
DP  - 2009 Oct 15
TI  - The hypoxic microenvironment maintains glioblastoma stem cells and promotes 
      reprogramming towards a cancer stem cell phenotype.
PG  - 3274-84
AB  - Glioblastomas are highly lethal cancers that contain cellular hierarchies with 
      self-renewing cancer stem cells that can propagate tumors in secondary transplant 
      assays. The potential significance of cancer stem cells in cancer biology has 
      been demonstrated by studies showing contributions to therapeutic resistance, 
      angiogenesis and tumor dispersal. We recently reported that physiologic oxygen 
      levels differentially induce hypoxia inducible factor-2alpha (HIF2alpha) levels 
      in cancer stem cells. HIF1alpha functioned in proliferation and survival of all 
      cancer cells but also was activated in normal neural progenitors suggesting a 
      potentially restricted therapeutic index while HIF2alpha was essential in only in 
      cancer stem cells and was not expressed by normal neural progenitors 
      demonstrating HIF2alpha is a cancer stem cell specific target. We now extend 
      these studies to examine the role of hypoxia in regulating tumor cell plasticity. 
      We find that hypoxia promotes the self-renewal capability of the stem and 
      non-stem population as well as promoting a more stem-like phenotype in the 
      non-stem population with increased neurosphere formation as well as upregulation 
      of important stem cell factors, such as OCT4, NANOG and c-MYC. The importance of 
      HIF2alpha was further supported as forced expression of non-degradable HIF2alpha 
      induced a cancer stem cell marker and augmented the tumorigenic potential of the 
      non-stem population. This novel finding may indicate a specific role of HIF2alpha 
      in promoting glioma tumorigenesis. The unexpected plasticity of the non-stem 
      glioma population and the stem-like phenotype emphasizes the importance of 
      developing therapeutic strategies targeting the microenvironmental influence on 
      the tumor in addition to cancer stem cells.
FAU - Heddleston, John M
AU  - Heddleston JM
AD  - Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, 
      Cleveland, OH, USA.
FAU - Li, Zhizhong
AU  - Li Z
FAU - McLendon, Roger E
AU  - McLendon RE
FAU - Hjelmeland, Anita B
AU  - Hjelmeland AB
FAU - Rich, Jeremy N
AU  - Rich JN
LA  - eng
GR  - NS054276/NS/NINDS NIH HHS/United States
GR  - R01 CA116659/CA/NCI NIH HHS/United States
GR  - R01 NS054276-03/NS/NINDS NIH HHS/United States
GR  - R01 CA116659-05/CA/NCI NIH HHS/United States
GR  - CA116659/CA/NCI NIH HHS/United States
GR  - K02 NS047409-04/NS/NINDS NIH HHS/United States
GR  - R01 CA129958-02/CA/NCI NIH HHS/United States
GR  - R01 CA129958/CA/NCI NIH HHS/United States
GR  - CA112958/CA/NCI NIH HHS/United States
GR  - R01 CA116659-04/CA/NCI NIH HHS/United States
GR  - K02 NS047409/NS/NINDS NIH HHS/United States
GR  - NS047409/NS/NINDS NIH HHS/United States
GR  - R01 NS054276/NS/NINDS NIH HHS/United States
GR  - R01 CA129958-01A1/CA/NCI NIH HHS/United States
GR  - R01 NS054276-04/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20091003
PL  - United States
TA  - Cell Cycle
JT  - Cell cycle (Georgetown, Tex.)
JID - 101137841
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (Homeodomain Proteins)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Nanog Homeobox Protein)
RN  - 0 (Nanog protein, mouse)
RN  - 0 (Octamer Transcription Factor-3)
RN  - 0 (Pou5f1 protein, mouse)
RN  - 0 (Proto-Oncogene Proteins c-myc)
RN  - 0 (RNA, Messenger)
RN  - 1B37H0967P (endothelial PAS domain-containing protein 1)
SB  - IM
MH  - Animals
MH  - Basic Helix-Loop-Helix Transcription Factors/metabolism
MH  - Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Glioblastoma/*metabolism
MH  - Homeodomain Proteins/metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
MH  - Mice
MH  - Mice, Nude
MH  - Nanog Homeobox Protein
MH  - Neoplastic Stem Cells/*metabolism
MH  - Octamer Transcription Factor-3/metabolism
MH  - Phenotype
MH  - Proto-Oncogene Proteins c-myc/metabolism
MH  - RNA, Messenger/metabolism
MH  - Transplantation, Heterologous
PMC - PMC2825672
MID - NIHMS165167
EDAT- 2009/09/23 06:00
MHDA- 2009/12/22 06:00
PMCR- 2010/10/15
CRDT- 2009/09/23 06:00
PHST- 2009/09/23 06:00 [entrez]
PHST- 2009/09/23 06:00 [pubmed]
PHST- 2009/12/22 06:00 [medline]
PHST- 2010/10/15 00:00 [pmc-release]
AID - 9701 [pii]
AID - 10.4161/cc.8.20.9701 [doi]
PST - ppublish
SO  - Cell Cycle. 2009 Oct 15;8(20):3274-84. doi: 10.4161/cc.8.20.9701. Epub 2009 Oct 
      3.