Quiescence as a mechanism for cyclical hypoxia and acidosis |
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Authors: | Kieran Smallbone David J Gavaghan Philip K Maini J Michael Brady |
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Institution: | (1) Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, 131 Princess Street, Manchester, M1 7DN, UK;(2) Oxford University Computing Laboratory, Parks Road, Oxford, OX1 3QD, UK;(3) Centre for Mathematical Biology, Mathematical Institute, University of Oxford, 24-29 St Giles’, Oxford, OX1 3LB, UK;(4) Department of Engineering Science, University of Oxford, Parks Road, Oxford, OX1 3PJ, UK |
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Abstract: | Tumour tissue characteristically experiences fluctuations in substrate supply. This unstable microenvironment drives constitutive metabolic changes within cellular populations and, ultimately, leads to a more aggressive phenotype. Previously, variations in substrate levels were assumed to occur through oscillations in the haemodynamics of nearby and distant blood vessels. In this paper we examine an alternative hypothesis, that cycles of metabolite concentrations are also driven by cycles of cellular quiescence and proliferation. Using a mathematical modelling approach, we show that the interdependence between cell cycle and the microenvironment will induce typical cycles with the period of order hours in tumour acidity and oxygenation. As a corollary, this means that the standard assumption of metabolites entering diffusive equilibrium around the tumour is not valid; instead temporal dynamics must be considered. |
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Keywords: | Acidity Hypoxia Delay differential equations |
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