Hypoxia is a common feature in
tumors associated with an increased resistance of
tumor cells to
therapies. In addition to O(2) diffusion-limited
hypoxia, another form of tumor hypoxia characterized by fluctuating changes in pO(2) 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-1alpha (HIF-1alpha)-targeting
small interfering RNA led us to document that the accumulation of HIF-1alpha 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-1alpha to resensitize the
tumor vasculature to anticancer treatments.