The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype
Open accessAbstract
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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Hypoxia can drive dedifferentiation of surgically derived GBM cells toward a stem-like phenotype at least partly via HIF-2α, not HIF-1α, since HIF-2α knockdown in glioma stem cells reduces tumor initiation in vivo.
“Hypoxia can induce dedifferentiation of surgically-derived GBM tumor cells to a more stem-like phenotype driven at least in part, through activation of HIF-2α, but not HIF-1α, as knockdown of HIF-2α (but not HIF-1α) in glioma stem cells inhibits their tumor initiating potential in vivo [45–48].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [45]
The section “HIF2α Promotes a Cancer Stem Cell State” supports the claim that HIF2α can promote a stem-like phenotype in non-stem glioblastoma cells. But “The Role of Hypoxia Inducible Factors in Cancer Stem Cell Self-Renewal and Tumor Growth” says stem cells with either HIF1α or HIF2α targeted failed to initiate tumors on xenotransplantation, contrary to the claim that HIF1α knockdown did not inhibit tumor initiation. Page numbers are unavailable in our copy. (LLM, conf=0.91)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredHigh HIF-2α protein in GBM correlates with shorter overall survival, while HIF-1α does not correlate with outcome.
“High levels of HIF-2α protein in GBM correlate to decreased OS, whereas HIF-1α is not correlated to outcome [45,46].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [45]
The Introduction section, “The Role of Hypoxia Inducible Factors in Cancer Stem Cell Self-Renewal and Tumor Growth” (page unavailable), reports that HIF2α, but not HIF1α, levels were associated with negative survival in a patient database. However, that analysis measured mRNA, not protein, so it does not establish the claimed protein-level correlation. (LLM, conf=0.88)
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- Authors
- Heddleston, J. M., Li, Z., McLendon, R. E., Hjelmeland, A. B., & Rich, J. N.
- Affiliations
- Cleveland Clinic (US)
- Duke University (US)
- Corresponding author
- Rich, Jeremy N.
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2009-10-15
- Volume
- 8
- Issue
- 20
- Pages
- 3274-3284
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- PMC
- PMC2825672
- OpenAlex
- W2051588629
- Cited by
- 813
- References
- 74
- Citations by year
- 2026: 20 · 2025: 25 · 2024: 25 · 2023: 35 · 2022: 40 · 2021: 51 · 2020: 42 · 2019: 42 · 2018: 48 · 2017: 61 · 2016: 71 · 2015: 63 · 2014: 61 · 2013: 64 · 2012: 69
- FWCI
- 18.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Cell Cycle (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA 116659, R01CA116659, CA112958, R01CA129958)
- National Institute of Neurological Disorders and Stroke (K02NS047409, R01NS054276, NS054276, NS047409)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- glioblastoma, cancer stem cells, hypoxia, HIF-2α, tumor microenvironment, cellular plasticity, self-renewal, neurosphere formation, Oct4, Nanog, c-Myc, HIF-1α, neural progenitor cells, tumorigenicity, treatment resistance
- MeSH terms
- Nanog Homeobox Protein, Endothelial PAS Domain-Containing Protein 1, Animals, Glioblastoma, Humans, Mice, Nude, Phenotype, RNA, Messenger, Transplantation, Heterologous, Neoplastic Stem Cells, Cell Hypoxia, Proto-Oncogene Proteins c-myc, Homeodomain Proteins, Cell Line, Tumor, Octamer Transcription Factor-3, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit
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