Abstract
Tumor recurrence frequently occurs after radiotherapy, but the characteristics, intratumoral localization, and post-irradiation behavior of radioresistant cancer cells, remain largely unknown. Here we developed a sophisticated strategy to track the post-irradiation fate of cells which existed in perinecrotic regions at the time of radiation, and obtained direct evidence in vivo that this population predominantly causes tumor recurrence. Although the perinecrotic tumor cells were originally hypoxia-inducible factor 1 (HIF-1)-negative, they obtained HIF-1 activity after surviving radiation, which triggered their translocation toward tumor blood vessels and subsequent tumor recurrence. A HIF-1 inhibitor suppressed the translocation and decreased the incidence of post-irradiation tumor recurrence. For the first time, our data unveil the HIF-1-dependent cellular dynamics behind post-irradiation tumor recurrence and provide a rational basis for targeting HIF-1 after radiation therapy.
