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Hypoxia-Inducible Factors Regulate Tumorigenic Capacity of Glioma Stem Cells
Open accessAbstract
Glioblastomas are lethal cancers characterized by florid angiogenesis promoted in part by glioma stem cells (GSCs). Because hypoxia regulates angiogenesis, we examined hypoxic responses in GSCs. We now demonstrate that hypoxia-inducible factor HIF2alpha and multiple HIF-regulated genes are preferentially expressed in GSCs in comparison to non-stem tumor cells and normal neural progenitors. In tumor specimens, HIF2alpha colocalizes with cancer stem cell markers. Targeting HIFs in GSCs inhibits self-renewal, proliferation, and survival in vitro, and attenuates tumor initiation potential of GSCs in vivo. Analysis of a molecular database reveals that HIF2A expression correlates with poor glioma patient survival. Our results demonstrate that GSCs differentially respond to hypoxia with distinct HIF induction patterns, and HIF2alpha might represent a promising target for antiglioblastoma therapies.
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“Since HIF-2α is strongly expressed in the cytoplasm of NB tumor cells at physiological oxygen levels (5% O2), this could suggest additional largely unexplored functions of HIF-2α in the cytoplasm, independent of HIF-1β-dependent transcription, such as regulation of mRNA translation [9,43].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [43]
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“In NB clinical specimens, HIF-1α expression negatively correlates with the presence of blood vessels indicating that HIF-1α is expressed exclusively in hypoxic cells [43].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [43]
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“However, HIF-2α is located in dense clusters of cells adjacent to blood vessels, referred to as the perivascular niche, which have a neural crest-like phenotype, and are HIF-1α negative, suggesting they are not hypoxic [43].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [43]
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“However, treatment with PT2385 had no effect on tumor growth, did not impact transcription of HIF target genes and did not modulate chemotherapy response [43].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [43]
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“Given that HIF-2α is an important transcription factor in cancer progression and leads to poor prognosis69,70”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [70]
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“Hypoxia was first shown to induce the CSC phenotype in glioma [77] and, subsequently, in breast cancer [78, 79], in a HIF-dependent manner.”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [77]
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Self-citation
Metadata
- Authors
- Li, Z., Bao, S., Wu, Q., Wang, H., Eyler, C., Sathornsumetee, S., Shi, Q., Cao, Y., Lathia, J., McLendon, R. E., Hjelmeland, A. B., & Rich, J. N.
- Affiliations
- Duke Medical Center (US)
- Cleveland Clinic (US)
- Corresponding author
- Rich, Jeremy N.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2009-06
- Volume
- 15
- Issue
- 6
- Pages
- 501-513
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC2693960
- OpenAlex
- W2039075677
- Cited by
- 1,354
- References
- 65
- Citations by year
- 2026: 41 · 2025: 40 · 2024: 49 · 2023: 72 · 2022: 92 · 2021: 98 · 2020: 72 · 2019: 75 · 2018: 74 · 2017: 93 · 2016: 97 · 2015: 97 · 2014: 96 · 2013: 80 · 2012: 101
- FWCI
- 30.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- 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 › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- HIF-2α, glioma stem cells, glioblastoma, hypoxia, angiogenesis, self-renewal, tumor initiation, cancer stem cell markers, patient survival, therapeutic target
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Brain Neoplasms, Cell Survival, Cells, Cultured, Glioblastoma, Humans, Mice, Inbred BALB C, Mice, Nude, Neoplasm Transplantation, Neovascularization, Pathologic, Stem Cells, Biomarkers, Tumor, Neoplastic Stem Cells, Cell Hypoxia, Vascular Endothelial Growth Factor A, Cell Proliferation, Mice, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit
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