Cited by 190Cancer, Hypoxia, and MetabolismAngiogenesis and VEGF in CancerCancer Cells and Metastasis

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Preconditioning of the Tumor Vasculature and Tumor Cells by Intermittent Hypoxia: Implications for Anticancer Therapies

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Martinive, Philippe, Defresne, Florence, Bouzin, Caroline, Saliez, Julie, Lair, Florence, Grégoire, Vincent, Michiels, Carine, Dessy, Chantal, Feron, Olivier·2006·Cancer Research

DOI 10.1158/0008-5472.can-06-2056

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Abstract

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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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);
ORCID: Martinive, Philippe
Defresne, Florence
Bouzin, Caroline
Michiels, Carine
Dessy, Chantal
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2006-12-15
Volume: 66
Issue: 24
Pages: 11736-11744
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-06-2056
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

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Preconditioning of the Tumor Vasculature and Tumor Cells by Intermittent Hypoxia: Implications for Anticancer Therapies

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