Abstract
BackgroundElucidating the effects of drugs on solid tumours is a highly challenging multi-level problem, since this involves many complexities associated with transport and cellular response, which in turn is characterized by highly non-linear chemical signal transduction. Appropriate systems frameworks are needed to seriously address the sources of these complexities, especially from the cellular side.ResultsWe develop a skeletal modelling framework incorporating interstitial drug transport, intracellular signal processing and cell population descriptions. The descriptions aim to appropriately capture the nature of information flow. The model is deliberately formulated to start with simple intracellular descriptions so that additional features can be incorporated in a modular fashion. Two kinds of intracellular signalling modules which describe the drug effect were considered, one a monostable switch and the other a bistable switch. Analysis of our model revealed how different drug stimuli can lead to cell killing in the tumour. Interestingly both modules considered exhibited similar trends. The effects of important parameters were also studied.ConclusionsWe have created a predictive systems platform integrating drug transport and cellular response which can be systematically augmented to include additional layers of cellular complexity. Our results indicate that intracellular signalling models which are qualitatively different can give rise to similar behaviour to simple (and typical) stimuli, and that validating intracellular descriptions must be performed with care by considering a variety of drug stimuli.
Highlights
Elucidating the effects of drugs on solid tumours is a highly challenging multi-level problem, since this involves many complexities associated with transport and cellular response, which in turn is characterized by highly nonlinear chemical signal transduction
We present the results of the analysis of our model by considering and contrasting the results for multiple variants of the intracellular signal transduction considered
Our approach is motivated by the desire to create an appropriate framework which is based on a dynamical systems underpinning, which can seriously tackle different aspects of the cellular complexity, and the non-linearity of cellular signal processing
Summary
Elucidating the effects of drugs on solid tumours is a highly challenging multi-level problem, since this involves many complexities associated with transport and cellular response, which in turn is characterized by highly nonlinear chemical signal transduction. The need to systematically understand the complex aspects of solid tumours is evident when one considers the potentially fatal consequences which are associated with solid tumours growing unchecked. Solid tumours are a highly complex mini-universe in themselves. They are typically fed by a complex vascular network which provides blood and nutrients. This vascular network is itself more complex and irregular than vascular networks in normal tissues. A growing tumour which is not vascularized, secretes chemicals which eventually lead to its vascularization by the process of tumour-induced angiogenesis
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