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Preconditioning of the Tumor Vasculature and Tumor Cells by Intermittent Hypoxia: Implications for Anticancer Therapies
Open accessAbstract
Hypoxia is a common feature in tumors associated with an increased resistance of tumor cells to therapies. In addition to O2 diffusion–limited hypoxia, another form of tumor hypoxia characterized by fluctuating changes in pO2 within the disorganized tumor vascular network is described. Here, we postulated that this form of intermittent hypoxia promotes endothelial cell survival, thereby extending the concept of hypoxia-driven resistance to the tumor vasculature. We found that endothelial cell exposure to cycles of hypoxia reoxygenation not only rendered them resistant to proapoptotic stresses, including serum deprivation and radiotherapy, but also increased their capacity to migrate and organize in tubes. By contrast, prolonged hypoxia failed to exert protective effects and even seemed deleterious when combined with radiotherapy. The use of hypoxia-inducible factor-1α (HIF-1α)–targeting small interfering RNA led us to document that the accumulation of HIF-1α during intermittent hypoxia accounted for the higher resistance of endothelial cells. We also used an in vivo approach to enforce intermittent hypoxia in tumor-bearing mice and found that it was associated with less radiation-induced apoptosis within both the vascular and the tumor cell compartments (versus normoxia or prolonged hypoxia). Radioresistance was further ascertained by an increased rate of tumor regrowth in irradiated mice preexposed to intermittent hypoxia and confirmed in vitro using distinctly radiosensitive tumor cell lines. In conclusion, we have documented that intermittent hypoxia may condition endothelial cells and tumor cells in such a way that they are more resistant to apoptosis and more prone to participate in tumor progression. Our observations also underscore the potential of drugs targeting HIF-1α to resensitize the tumor vasculature to anticancer treatments. (Cancer Res 2006; 66(24): 11736-44)
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“These mechanisms include a decrease in topo alpha mRNA and protein,878 changes in proteasome function,879 and small interfering RNA.880”
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“(2) CIH results in molecular changes that promote cancer progression or metastases.”
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“In vitro models have provided two main findings: (1) CIH results in changes that are distinct from sustained hypoxia;”
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“Other studies focused on why cancer cells exposed to CIH may be more resistant to therapy.”
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Metadata
- Authors
- Martinive, P., Defresne, F., Bouzin, C., Saliez, J., Lair, F., Grégoire, V., Michiels, C., Dessy, C., & Feron, O.
- Affiliations
- UCLouvain (BE)
- 2Center for Molecular Imaging and Experimental Radiotherapy, Brussels, Belgium; and
- University of Namur (BE)
- 1Unit of Pharmacology and Therapeutics (FATH 5349), Université Catholique de Louvain (UCL);
- Venue
- Cancer Research
- Published
- 2006-12-15
- Volume
- 66
- Issue
- 24
- Pages
- 11736-11744
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2151713230
- Semantic Scholar
- 6e13dac6f9dae03ad2cb789557b6f9e7d3000bb7
- Cited by
- 190
- References
- 45
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 11 · 2022: 6 · 2021: 6 · 2020: 15 · 2019: 5 · 2018: 5 · 2017: 9 · 2016: 15 · 2015: 17 · 2014: 11 · 2013: 8 · 2012: 12
- FWCI
- 4.90
- Type
- journal article
- Language
- en
- Open access
- green
- orbi.uliege.be
- Licence
- other-oa
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Repository of the University of Namur (publishedVersion)
- Open Repository and Bibliography (University of Liège) (submittedVersion, other-oa)
- Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion)
- DIAL (Catholic University of Leuven) (submittedVersion)
- Funders
- Fonds De La Recherche Scientifique - FNRS
- Topics
- 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
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- intermittent hypoxia, tumor hypoxia, tumor vasculature, endothelial cells, hypoxia/reoxygenation, radioresistance (biology), HIF-1α, apoptosis, tumor cell migration, tumor angiogenesis, tumor regrowth, radiosensitization, siRNA
- MeSH terms
- Animals, Cell Division, Humans, Liver Neoplasms, Male, Mice, Inbred Strains, Neovascularization, Pathologic, Cell Hypoxia, Ischemic Preconditioning, Cell Line, Tumor, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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