  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 R and Milotti E, Phys. Biol. 2 (2005) 8-22). 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 - that 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 behaviour of cells grown in a glucose-poor
medium: these predictions are confirmed by experimental observation.
