Abstract
Hypoxia-inducible factor-1 (HIF-1) plays important roles in angiogenesis, invasion and metastasis of cancer cells, and change of metabolic process from oxidative phosphorylation to glycolysis in response to hypoxia. In addition, it was recently reported that the level of HIF-1 activity is a significant predictor for tumor recurrence after radiation therapy. However, the molecular mechanism underlying the HIF-1-mediated radioresistance remains to be elucidated. The purpose of this study is to approach to the problem. Growth delay assays showed that HIF-1-targeting treatment with a protein drug, TOP3, or with a gene therapy strategy, Ad/5HREp-BCD, increased the effect radiation therapy in vivo, while siRNA-mediated modulation of HIF-1 activity in vitro showed little effect on radiosensitivity of cultured cells. Based on these results, we hypothesized that HIF-1-active tumor cells are radiosensitive, but they have a property to facilitate the radioresistance of the other constituents of tumors. To examine the possibility, we established a unique system to tag the HIF-1-active cells in tumor xenografts and chased the fate of them after radiation therapy. The optical imaging experiment clearly showed that HIF-1-active cells were predictably radiosensitive and recurrent tumors were mainly composed of the tag-free tumor cells. We are now examining the next hypothesis that HIF-1-active cells protect endothelial cells from cytotoxic effect of radiation, because TOP3 dramatically decreased micro vessel density in tumor xenografts after radiation treatment. In the present study, we present our latest data in this field and propose a model underlying the HIF-1-mediated tumor radioresistance.
