Systems biological and mechanistic modelling of radiation-induced cancer

Abstract

This paper summarises the five presentations at the First International Workshop on Systems Radiation Biology that were concerned with mechanistic models for carcinogenesis. The mathematical description of various hypotheses about the carcinogenic process, and its comparison with available data is an example of systems biology. It promises better understanding of effects at the whole body level based on properties of cells and signalling mechanisms between them. Of these five presentations, three dealt with multistage carcinogenesis within the framework of stochastic multistage clonal expansion models, another presented a deterministic multistage model incorporating chromosomal aberrations and neoplastic transformation, and the last presented a model of DNA double-strand break repair pathways for second breast cancers following radiation therapy.

Fig. 1

Estimate of the lifetime excess relative risk per nominal exposure unit of rats exposed to radon for various periods of time with a constant exposure rate (100 WL). The dashed line represents model estimates with only an initiating radiation action (I-model), and the solid line one with initiation and promotion (IP-model) (based on model fits carried out by Heidenreich et al. [24])

Fig. 2

Number of lung cancer cases in mice after acute exposure to gamma-rays and neutrons (based on model fits carried out by Heidenreich et al. [18])

Fig. 3

Schematic diagram of generalized MVK model with k cancer-stage mutations and m destabilizing mutations, as developed by Little and Wright [36]

Fig. 4

Cancer hazards predicted by models of Nowak et al. [35] (with two cancer-stage mutations and one destabilizing mutation), Luebeck and Moolgavkar [5] (with four cancer-stage mutations and no destabilizing mutations), and Little and Wright [36] (with two cancer-stage mutations and one destabilizing mutation, three cancer-stage mutations and one destabilizing mutation, five cancer-stage mutations and two destabilizing mutations), with stem cell population fixed to 10⁸ cells, refitted to SEER [41] colon cancer data, and observed data (with 95% CI, adjusted for overdispersion) (reproduced from Little and Li [40])

Fig. 5

Transformation frequency for CGL1 cells irradiated with γ-radiation [45]. Error bars represent 95% CI. a Data for immediate plating and SVM fit showing the three different contributions (dash line direct, dotted line bystander, solid line total). The direct contribution relates to a model fit with k_ap = 0 to control and high dose data for delayed and immediate plating [51]. The contribution of the bystanders was calculated as the difference between the direct and the total contribution. b Data for delayed plating and SVM fit showing the three different contributions (dash line direct, dotted line bystander, solid line total). For the SVM fits denoted as “total”, the 95% CI are shown for the low doses (dash–dot). Insets low-dose range with the x-axis units in Gy (reproduced from Schöllnberger et al. [51])