Tumor radioresistance caused by radiation-induced changes of stem-like cell content and sub-lethal damage repair capability

Fukui, Roman*; Saga, Ryo*; Matsuya, Yusuke  ; Tomita, Kazuo*; Kuwahara, Yoshikazu*; Ouchi, Kentaro*; Sato, Tomoaki*; Okumura, Kazuhiko*; Date, Hiroyuki*; Fukumoto, Manabu*; Hosokawa, Yoichiro*

Alive cancer cells after fractionated irradiations with 2 Gy X-rays per day for more than 30 days show clinically relevant radioresistant. Such radioresistance is experimentally interpreted to attributed to the increment of stem-like cell content. However, only an experimental approach cannot clarify the cell responses (DNA damage and cell death induction) of cancer stem cells, so the radioresistant mechanisms remain uncertain. In addition to the conventional cell experiments using radio-resistant cell lines established after fractionated irradiations, in this study we developed a mathematical model (so called integrated microdosimetric-kinetic (IMK) model) explicitly considering cancer stem-like cell content and DNA damage responses and investigated radioresistant mechanisms acquired after fractionated irradiations. The IMK model analysis suggested that the changes of stem-like cell fraction and DNA repair efficiency play important roles of radioresisitance acquired after irradiations. Considering these into the IMK model, we successfully reproduced the experimental survival of various cell lines and various irradiation conditions. This work would contribute to not only the precise understanding of the radioresistant mechanisms induced after irradiation but also predicting curative effects with high precision.