Recent advances in radiotherapy technology now enable us to deliver a booster dose of radiation to small target fractions in a malignant tumor. To fully exploit this technology in cancer therapy, it is necessary to clarify the location and dynamics of radioresistant cells in heterogeneous tumor microenvironments. Tumor cells in which the transcriptional activity of hypoxia-inducible factor 1 (HIF-1) is extremely high are recognized as potential targets, because HIF-1 has been strongly associated with tumor angiogenesis, invasion, metastasis, and poor prognosis after radiation therapy. In this review, we focus on recent advances in our understanding of  the molecular mechanism underlying the regulation of HIF-1s transcriptional activity,  the influence of radiation-induced alterations of the tumor microenvironment on intratumor HIF-1 activity,  HIF-1-mediated tumor radioresistance, and  an optimal treatment protocol for the combination of a HIF-1 inhibitor and radiation therapy.
Keywords: Radiation Therapy, tumor hypoxia, tumor microenvironment, hypoxia-inducible factor 1 (HIF-1), reoxygenation, radioresistance, ROS, reactive oxygen species
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