It has long been considered that chronic hypoxia, rather than cycling hypoxia, plays the main role in promotion of cancer progression and in the efficacy of radiation therapy or chemotherapy. This is because the major phenotypic shift associated with chronic hypoxia involves tumor cell resistance to chemotherapy or radiotherapy in addition to more invasive and metastatic features. However, this concept contradicts previous findings that tumor recurrence after radiation therapy tended to occur more frequently in regions where there was a high incidence of intermittent vascular stasis. Therefore, cyclically hypoxic cells might be the most radio-resistant cells and could therefore be responsible for tumor re-growth. The purpose of this study is to investigate the differential effect and mechanism of chronic and cycling hypoxia on tumor progression and tumor radio-sensitivity in the human glioblastoma
tumor model. We exposed GBM cells and mice bearing glioma to
experimentally imposed cycling or chronic hypoxic stress in vitro and
in vivo prior to treatment with ionizing irradiation. Cell proliferation assay, migration assay, invasion assay, clonogenic survival assay and tumor growth measurements were performed to determine tumor progression and tumor radiosensitivity. Furthermore, Tempol, a membrane-permeable radical scavenger, was used to determine the impact of reactive oxygen species (ROS) on hypoxia-induced tumor progression and radioresistance. In the present study, we identified a direct causal link between cycling hypoxia and tumor radiosensitivity in GBM and documented the differential effects of chronic versus cycling hypoxia in this process. Here, our results demonstrate that cycling hypoxia increases tumor cell proliferation, migration, invasion and
radioresistance by inducing ROS production. Tempol treatment during cycling hypoxia suppressed cycling hypoxia-induced tumor progression and radioresistance. These results have potentially important clinical
implications and suggest that ROS scavengers may be an effective approach by which to suppress hypoxia-induced tumor progression and radioresistance.
