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HIF-2α maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells
Open accessAbstract
High hypoxia-inducible factor-2α (HIF-2α) protein levels predict poor outcome in neuroblastoma, and hypoxia dedifferentiates cultured neuroblastoma cells toward a neural crest-like phenotype. Here, we identify HIF-2α as a marker of normoxic neural crest-like neuroblastoma tumor-initiating/stem cells (TICs) isolated from patient bone marrows. Knockdown of HIF-2α reduced VEGF expression and induced partial sympathetic neuronal differentiation when these TICs were grown in vitro under stem cell-promoting conditions. Xenograft tumors of HIF-2α-silenced cells were widely necrotic, poorly vascularized, and resembled the bulk of tumor cells in clinical neuroblastomas by expressing additional sympathetic neuronal markers, whereas control tumors were immature, well-vascularized, and stroma-rich. Thus, HIF-2α maintains an undifferentiated state of neuroblastoma TICs. Because low differentiation is associated with poor outcome and angiogenesis is crucial for tumor growth, HIF-2α is an attractive target for neuroblastoma therapy.
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“HIF-2α knockdown in glioblastoma and neuroblastoma results in poorly vascularized tumors (Li et al., 2009;Pietras et al., 2009).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Pietras et al., 2009
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“Furthermore, HIF-1α loss decreases tumor vascularization and impairs vascular function (Carmeliet et al., 1998), and HIF-2α knockdown in glioblastoma and neuroblastoma results in poorly vascularized tumors (Li et al., 2009; Pietras et al., 2009).”
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Metadata
- Authors
- Pietras, A., Hansford, L. M., Johnsson, A. S., Bridges, E., Sjölund, J., Gisselsson, D., Rehn, M., Beckman, S., Noguera, R., Navarro, S., Cammenga, J., Fredlund, E., Kaplan, D. R., & Påhlman, S.
- Affiliations
- Lund University (SE)
- University of Toronto (CA)
- Departments of cClinical Genetics and
- Universitat de València (ES)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-09-29
- Volume
- 106
- Issue
- 39
- Pages
- 16805-16810
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2745331
- OpenAlex
- W1967063990
- Cited by
- 135
- References
- 32
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 4 · 2022: 5 · 2021: 6 · 2020: 10 · 2019: 5 · 2018: 11 · 2017: 13 · 2016: 9 · 2015: 8 · 2014: 11 · 2013: 10 · 2012: 14
- FWCI
- 8.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Neuroblastoma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- HIF-2α, neuroblastoma, cancer stem cells, neural crest-like cells, hypoxia, neuronal differentiation, vascular endothelial growth factor, tumor angiogenesis, tumor necrosis, bone marrow, stem cell niche, therapeutic target
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Cell Differentiation, Female, Humans, Mice, Nude, Neural Crest, Neuroblastoma, Down-Regulation, Cell Hypoxia, Vascular Endothelial Growth Factors, Cell Line, Tumor, Mice, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors
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