This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Martinive, P. Articles by Feron, O. Search for Related Content PubMed PubMed Citation Articles by Martinive, P. Articles by Feron, O.

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

¹ Unit of Pharmacology and Therapeutics (FATH 5349), Université Catholique de Louvain (UCL); ² Center for Molecular Imaging and Experimental Radiotherapy, Brussels, Belgium; and ³ Laboratory of Biochemistry and Cellular Biology, University of Namur, Namur, Belgium

Requests for reprints: Olivier Feron, Unit of Pharmacology and Therapeutics (FATH 5349), University of Louvain Medical School, 52 Avenue East Mounier, B-1200 Brussels, Belgium. Phone: 32-2-764-5264; Fax: 32-2-764-5261; E-mail: feron{at}mint.ucl.ac.be.

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-1 (HIF-1)–targeting small interfering RNA led us to document that the accumulation of HIF-1 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-1 to resensitize the tumor vasculature to anticancer treatments. (Cancer Res 2006; 66(24): 11736-44)

This article has been cited by other articles:

				F. Frerart, I. Lobysheva, B. Gallez, C. Dessy, and O. Feron Vascular Caveolin Deficiency Supports the Angiogenic Effects of Nitrite, a Major End Product of Nitric Oxide Metabolism in Tumors Mol. Cancer Res., July 1, 2009; 7(7): 1056 - 1063. [Abstract] [Full Text] [PDF]

				J. F. Garvey, C. T. Taylor, and W. T. McNicholas Cardiovascular disease in obstructive sleep apnoea syndrome: the role of intermittent hypoxia and inflammation Eur. Respir. J., May 1, 2009; 33(5): 1195 - 1205. [Abstract] [Full Text] [PDF]

				J.-L. Balligand, O. Feron, and C. Dessy eNOS Activation by Physical Forces: From Short-Term Regulation of Contraction to Chronic Remodeling of Cardiovascular Tissues Physiol Rev, April 1, 2009; 89(2): 481 - 534. [Abstract] [Full Text] [PDF]

				R. Wirthner, S. Wrann, K. Balamurugan, R. H. Wenger, and D. P. Stiehl Impaired DNA double-strand break repair contributes to chemoresistance in HIF-1{alpha}-deficient mouse embryonic fibroblasts Carcinogenesis, December 1, 2008; 29(12): 2306 - 2316. [Abstract] [Full Text] [PDF]

				L. I. Cardenas-Navia, D. Mace, R. A. Richardson, D. F. Wilson, S. Shan, and M. W. Dewhirst The Pervasive Presence of Fluctuating Oxygenation in Tumors Cancer Res., July 15, 2008; 68(14): 5812 - 5819. [Abstract] [Full Text] [PDF]

				O. Tredan, C. M. Galmarini, K. Patel, and I. F. Tannock Drug Resistance and the Solid Tumor Microenvironment J Natl Cancer Inst, October 3, 2007; 99(19): 1441 - 1454. [Abstract] [Full Text] [PDF]

				M. W. Dewhirst Intermittent Hypoxia Furthers the Rationale for Hypoxia-Inducible Factor-1 Targeting Cancer Res., February 1, 2007; 67(3): 854 - 855. [Abstract] [Full Text] [PDF]