Microenvironmental variables must influence intrinsic phenotypic parameters of cancer stem cells to affect tumourigenicity

Abstract

Since the discovery of tumour initiating cells (TICs) in solid tumours, studies focussing on their role in cancer initiation and progression have abounded. The biological interrogation of these cells continues to yield volumes of information on their pro-tumourigenic behaviour, but actionable generalised conclusions have been scarce. Further, new information suggesting a dependence of tumour composition and growth on the microenvironment has yet to be studied theoretically. To address this point, we created a hybrid, discrete/continuous computational cellular automaton model of a generalised stem-cell driven tissue with a simple microenvironment. Using the model we explored the phenotypic traits inherent to the tumour initiating cells and the effect of the microenvironment on tissue growth. We identify the regions in phenotype parameter space where TICs are able to cause a disruption in homeostasis, leading to tissue overgrowth and tumour maintenance. As our parameters and model are non-specific, they could apply to any tissue TIC and do not assume specific genetic mutations. Targeting these phenotypic traits could represent a generalizable therapeutic strategy across cancer types. Further, we find that the microenvironmental variable does not strongly effect the outcomes, suggesting a need for direct feedback from the microenvironment onto stem-cell behaviour in future modelling endeavours.\n\nAuthor SummaryIn this paper, we present a mathematical/computational model of a tumour growing according to the canonical cancer stem-cell hypothesis with a simplified microenvironment. We explore the parameters of this model and find good agreement between our model and other theoretical models in terms of the intrinsic cellular parameters, which are difficult to study biologically. We find, however, disagreement between novel biological data and our model in terms of the microenvironmental changes. We conclude that future theoretical models of stem-cell driven tumours must include specific feedback from the microenvironment onto the individual cellular behavior. Further, we identify several cell intrinsic parameters which govern loss of homeostasis into a state of uncontrolled growth.