Stochastic cellular automata model of tumorous neurosphere growth: Roles of developmental maturity and cell death

Abstract

The neurosphere assay is a powerful in vitro system for studying stem/progenitor-cell-driven tissue growth. By employing a stochastic cellular automata model, we simulated the development of tumorous neurospheres in response to transformation of a randomly selected progenitor cell into a brain tumor stem cell. Simulated tumorous neurospheres were distinguished from normal neurospheres by their size, which exceeded that of normal neurospheres typically manifold. A decisive factor that determined whether brain tumor stem cells gave rise to tumorous neurospheres was their ability to escape encapsulation by neighboring cells, which suppressed mitotic activity through contact inhibition. In our simulations, the likelihood of tumorigenesis was strongly negatively correlated with the developmental maturity of the neurospheres in which the transformation of a progenitor cell into a brain tumor stem cell was induced. This likelihood was furthermore modulated by the probability of the progeny of dividing cells to undergo cell death. In developmentally immature neurospheres, the number of normal neurospheres, relative to the number of tumorous neurospheres, increased with increasing cell death probability. Markedly, in developmentally mature neurospheres the opposite effect was observed. This dichotomous effect of cell death on simulated tumor progression provides theoretical support for the seemingly paradoxical finding made by other authors in experimental studies that anti-cancer therapies based on induction of apoptosis may both promote and suppress tumor growth.