A Mathematical model of modification of cell-cycle progression by radiation-induced bystander effects

Hattori, Yuya; Yokoya, Akinari; Watanabe, Ritsuko

It is widely recognized that bystander phenomena are caused by two intercellular signaling pathways, via culture medium and gap junctions. We consider that modeling the bystander effect on cell-cycle progression is the first step toward investigating the mechanism of transgenerational effects, which ultimately trigger radiation-induced carcinogenesis. Our model describes the cultured cellular population as two-dimensional grids. The simulation algorithm consists of four steps: (1) irradiation, (2) generation and diffusion of intercellular signals, (3) induction of DNA damage by direct irradiation and intercellular signals, (4) response on cell cycle for DNA damage. The cell cycle is represented as a virtual clock that includes several checkpoint pathways within a cyclic process. Using this model, we simulated how affect the intercellular signals on cellular responses in sparsely and densely cultured conditions. In this work, we adopted life-time and diffusion constant of cytokine and calcium ion for signals via culture medium and signals via gap-junction, respectively. The simulation shows that the signals increased cell-cycle modification with increase of dose. The bystander effect on cell-cycle was significant for cells in sparse condition than in dense condition, showing that the model works reasonably. However, the effect of signals via gap-junction was unexpectedly small. It was caused by the short life-time of calcium ion. It indicates that other mechanism as reemission of other substances should be considered for the model of gap-junction. Obtaining the experimental data comparable with our simulation can be of great help to understand the mechanism of bystander effect.