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In radiotherapy, cancer stem cells (CSCs) are well recognized as one of the radioresistant cell types. Even in a small subpopulation, CSCs may have an influence on tumor control probability, represented by cell killing after irradiation. However, the relationship between the percentage content of CSCs and the cell survival dose–response curve has not yet been quantitatively clarified. In this study, we developed a cell-killing model for two cell populations (CSCs and progeny cells) to predict the surviving fractions, and compared it with the conventional linear–quadratic (LQ) model. Three prostate cancer cell lines (DU145, PC3 and LNCaP) were exposed to X-rays at doses ranging from 0 to 10 Gy. After the irradiation, we performed clonogenic survival assays to generate the cell survival curves, and carried out flow-cytometric analyses to estimate the percentage content of CSCs for each cell line. The cell survival curves for DU145 cells and PC3 cells seemed not to follow the conventional LQ model in the high dose range (>8 Gy). However, the outputs of the developed model agreed better with the experimental cell survival curves than those of the LQ model. The percentage content of CSCs predicted by the developed model was almost coincident with the measured percentage content for both DU145 cells and PC3 cells. The experiments and model analyses indicate that a small subpopulation of radioresistant CSCs has lower radiosensitivity in the high-dose range, which may lessen the clinical outcome for patients with prostate cancer after high-dose radiation therapy.

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Acquisition of radioresistance (RR) has been reported during cancer treatment with fractionated irradiation. However, RR is poorly understood in the prognosis of radiotherapy. Although radiotherapy is important in the treatment of prostate cancer (PCa), acquisition of RR has been reported in PCa with an increased number of cancer stem cells (CSCs), neuroendocrine differentiation (NED) and epithelial-mesenchymal transition. However, to the best of our knowledge, the mechanism underlying RR acquisition during fractionated irradiation remains unclear. In the present study, human PCa cell lines were subjected to fractionated irradiation according to a fixed schedule as follows: Irradiation (IR)1, 2 Gy/day with a total of 20 Gy; IR2, 4 Gy/day with a total of 20 Gy; and IR3, 4 Gy/day with a total of 56 Gy. The expression of cluster of differentiation (CD)44, a CSC marker, was identified to be increased by fractionated irradiation, particularly in DU145 cells. The expression levels of CD133 and CD138 were increased compared with those in parental cells following a single irradiation or multiple irradiations; however, the expression levels decreased with subsequent irradiation. RR was evidently acquired by exposure to 56 Gy radiation, which resulted in increased expression of the NED markers CD133 and CD138, and increased mRNA expression levels of the pluripotency-associated genes octamer-binding transcription factor 4 and Nanog homeobox. These data indicate that radiation-induced CSCs emerge due to the exposure of cells to fractionated irradiation. In addition, the consequent increase in the expression of NED markers is possibly induced by the increased expression of pluripotency-associated genes. Therefore, it can be suggested that cancer cells acquire RR due to increased expression of pluripotency-associated genes following exposure to fractionated irradiation.

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