Hypoxia-Inducible Factors, Stem Cells, and Cancer
Open accessAbstract
Regions of severe oxygen deprivation (hypoxia) arise in tumors due to rapid cell division and aberrant blood vessel formation. The hypoxia-inducible factors (HIFs) mediate transcriptional responses to localized hypoxia in normal tissues and in cancers and can promote tumor progression by altering cellular metabolism and stimulating angiogenesis. Recently, HIFs have been shown to activate specific signaling pathways such as Notch and the expression of transcription factors such as Oct4 that control stem cell self renewal and multipotency. As many cancers are thought to develop from a small number of transformed, self-renewing, and multipotent "cancer stem cells," these results suggest new roles for HIFs in tumor progression.
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The stem cell-like state is mediated by upregulation of OCT4, Notch, c-Myc, and telomerase.
“The stem cell-like state is mediated by upregulation of OCT4, Notch, c-Myc, and telomerase (Keith & Simon, 2007).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Keith & Simon, 2007
Figure 3 proposes that HIF activity in some hypoxic tumor cells could enhance the activity or expression of Notch, Oct4, c-Myc, and telomerase, potentially contributing to stem cell-like properties. The claim overstates this proposed mechanism as established and describes all four as upregulated, whereas the figure says their activity or expression could be enhanced. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHIF activation drives tumor progression by coordinating transcriptional programs that promote glycolytic metabolism, angiogenic factor production, cell survival, proliferation, immune evasion, and maintenance of cancer stem-like properties.
“From a mechanistic standpoint, HIF activation drives tumor progression by coordinating transcriptional programs that promote glycolytic metabolism, angiogenic factor production, cell survival, proliferation, immune evasion, and maintenance of cancer stem like properties [20,250,251].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [251]
The author manuscript and Figure 1 describe HIF-regulated genes involved in glycolysis and angiogenesis, while the cancer-stem-cell section discusses effects on survival and context-dependent proliferation. But Figure 3 presents acquisition of stem-like properties as a proposed model, not established maintenance, and the passages found do not link HIF activation to immune evasion. (LLM, conf=0.88)
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- Authors
- Keith, B., & Simon, M. C.
- Affiliations
- University of Pennsylvania (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Keith, Brian
- Simon, M. Celeste
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2007-05
- Volume
- 129
- Issue
- 3
- Pages
- 465-472
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3150586
- OpenAlex
- W1973541913
- Cited by
- 1,179
- References
- 59
- Citations by year
- 2026: 32 · 2025: 49 · 2024: 54 · 2023: 49 · 2022: 68 · 2021: 62 · 2020: 62 · 2019: 58 · 2018: 62 · 2017: 74 · 2016: 63 · 2015: 81 · 2014: 84 · 2013: 80 · 2012: 72
- FWCI
- 4.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2269 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL66130, R01HL066130)
- Core Research for Evolutional Science and Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- hypoxia-inducible factor, tumor hypoxia, cancer stem cells, stem cell self-renewal, tumor angiogenesis, Notch signaling, Oct4, tumor progression, cellular metabolism, transcriptional regulation
- MeSH terms
- Animals, Hypoxia, Humans, Neoplasms, Stem Cells, Neoplastic Stem Cells, Signal Transduction, Cell Hypoxia, Disease Progression, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins
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