How Can We Overcome Tumor Hypoxia in Radiation Therapy?

Local recurrence and distant metastasis frequently occur after radiation therapy for cancer and can be fatal. Evidence obtained from radiochemical and radiobiological studies has revealed these problems to be caused, at least in part, by a tumor-specific microenvironment, hypoxia. Moreover, a transcription factor, hypoxia-inducible factor 1 (HIF-1), was identified as pivotal to hypoxia-mediated radioresistance. To overcome the problems, radiation oncologists have recently obtained powerful tools, such as "simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT), which enables a booster dose of radiation to be delivered to small target fractions in a malignant tumor", "hypoxia-selective cytotoxins/drugs", and "HIF-1 inhibitors" etc. In order to fully exploit these innovative and interdisciplinary strategies in cancer therapy, it is critical to unveil the characteristics, intratumoral localization, and dynamics of hypoxia/HIF-1-active tumor cells during tumor growth and after radiation therapy. We have performed optical imaging experiments using tumor-bearing mice and revealed that the locations of HIF-1-active tumor cells changes dramatically as tumors grow. Moreover, HIF-1 activity changes markedly after radiation therapy. This review overviews 1) fundamental problems surrounding tumor hypoxia in current radiation therapy, 2) the function of HIF-1 in tumor radioresistance, 3) the dynamics of hypoxic tumor cells during tumor growth and after radiation therapy, and 4) how we should overcome the difficulties with radiation therapy using innovative interdisciplinary technologies.