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

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 +1 more·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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  • Mechanisms of this resistance include decreased topo alpha mRNA and protein, changes in proteasome function, and small interfering RNA.

    “These mechanisms include a decrease in topo alpha mRNA and protein,878 changes in proteasome function,879 and small interfering RNA.880”

    From International Consensus Statement on Obstructive Sleep Apnea (2023) · cites this paper as [880]

    Citation 880 is attached to the small-interfering-RNA portion of the sentence, not the topo alpha or proteasome claims. The Results and Discussion (page numbers not provided) describe HIF-1α-targeting siRNA as an intervention that prevents intermittent-hypoxia-associated resistance, rather than a mechanism that produces it. (LLM, conf=0.85)

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  • In vitro models have shown that cyclical intermittent hypoxia produces molecular changes that promote cancer progression or metastases.

    “(2) CIH results in molecular changes that promote cancer progression or metastases.”

    From International Consensus Statement on Obstructive Sleep Apnea (2023) · cites this paper as [880]

  • In vitro models have shown that cyclical intermittent hypoxia produces changes distinct from sustained hypoxia.

    “In vitro models have provided two main findings: (1) CIH results in changes that are distinct from sustained hypoxia;”

    From International Consensus Statement on Obstructive Sleep Apnea (2023) · cites this paper as [880]

  • Cancer cells exposed to cyclical intermittent hypoxia may be more resistant to therapy.

    “Other studies focused on why cancer cells exposed to CIH may be more resistant to therapy.”

    From International Consensus Statement on Obstructive Sleep Apnea (2023) · cites this paper as [880]

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Research works printed but not linked: 1

  1. [26]26. Rofstad EK. Microenvironment-induced cancer me- tastasis. Int J Radiat Biol 2000;76:589-605.

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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
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
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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