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The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype.

Publication ,  Journal Article
Heddleston, JM; Li, Z; McLendon, RE; Hjelmeland, AB; Rich, JN
Published in: Cell Cycle
October 15, 2009

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.

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Published In

Cell Cycle

DOI

EISSN

1551-4005

Publication Date

October 15, 2009

Volume

8

Issue

20

Start / End Page

3274 / 3284

Location

United States

Related Subject Headings

  • Transplantation, Heterologous
  • RNA, Messenger
  • Proto-Oncogene Proteins c-myc
  • Phenotype
  • Octamer Transcription Factor-3
  • Neoplastic Stem Cells
  • Nanog Homeobox Protein
  • Mice, Nude
  • Mice
  • Hypoxia-Inducible Factor 1, alpha Subunit
 

Citation

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Heddleston, J. M., Li, Z., McLendon, R. E., Hjelmeland, A. B., & Rich, J. N. (2009). The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle, 8(20), 3274–3284. https://doi.org/10.4161/cc.8.20.9701
Heddleston, John M., Zhizhong Li, Roger E. McLendon, Anita B. Hjelmeland, and Jeremy N. Rich. “The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype.Cell Cycle 8, no. 20 (October 15, 2009): 3274–84. https://doi.org/10.4161/cc.8.20.9701.
Heddleston JM, Li Z, McLendon RE, Hjelmeland AB, Rich JN. The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle. 2009 Oct 15;8(20):3274–84.
Heddleston, John M., et al. “The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype.Cell Cycle, vol. 8, no. 20, Oct. 2009, pp. 3274–84. Pubmed, doi:10.4161/cc.8.20.9701.
Heddleston JM, Li Z, McLendon RE, Hjelmeland AB, Rich JN. The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle. 2009 Oct 15;8(20):3274–3284.

Published In

Cell Cycle

DOI

EISSN

1551-4005

Publication Date

October 15, 2009

Volume

8

Issue

20

Start / End Page

3274 / 3284

Location

United States

Related Subject Headings

  • Transplantation, Heterologous
  • RNA, Messenger
  • Proto-Oncogene Proteins c-myc
  • Phenotype
  • Octamer Transcription Factor-3
  • Neoplastic Stem Cells
  • Nanog Homeobox Protein
  • Mice, Nude
  • Mice
  • Hypoxia-Inducible Factor 1, alpha Subunit