Ab initio phenomenological simulation of the growth of large tumor cell populations.

In a previous paper we have introduced a phenomenological model of cell metabolism and of the cell cycle to simulate the behavior of large tumor cell populations (Chignola and Milotti 2005 Phys. Biol. 2 8). Here we describe a refined and extended version of the model that includes some of the complex interactions between cells and their surrounding environment. The present version takes into consideration several additional energy-consuming biochemical pathways such as protein and DNA synthesis, the tuning of extracellular pH and of the cell membrane potential. The control of the cell cycle, which was previously modeled by means of ad hoc thresholds, has been directly addressed here by considering checkpoints from proteins that act as targets for phosphorylation on multiple sites. As simulated cells grow, they can now modify the chemical composition of the surrounding environment which in turn acts as a feedback mechanism to tune cell metabolism and hence cell proliferation: in this way we obtain growth curves that match quite well those observed in vitro with human leukemia cell lines. The model is strongly constrained and returns results that can be directly compared with actual experiments, because it uses parameter values in narrow ranges estimated from experimental data, and in perspective we hope to utilize it to develop in silico studies of the growth of very large tumor cell populations (10(6) cells or more) and to support experimental research. In particular, the program is used here to make predictions on the behavior of cells grown in a glucose-poor medium: these predictions are confirmed by experimental observation.