Heterogeneity and proliferation of invasive cancer subclones in game theory models of the Warburg effect

Marco Archetti

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21 Citations (Scopus)
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Abstract

OBJECTIVES: The Warburg effect, the switch from aerobic energy production to anaerobic glycolysis, promotes tumour proliferation and motility by inducing acidification of the tumour microenvironment. Therapies that reduce acidity could impair tumour growth and invasiveness. I analyse the dynamics of cell proliferation and of resistance to therapies that target acidity in a population of cells under the Warburg effect.
MATERIALS AND METHODS: The dynamics of mutant cells with increased glycolysis and motility is analysed in a multi-player game with collective interactions in the framework of evolutionary game theory. Perturbations of the level of acidity in the microenvironment are used to simulate the effect of therapies that target glycolysis.
RESULTS: The non-linear effects of glycolysis induce frequency-dependent clonal selection leading to the coexistence of glycolytic and non-glycolytic cells within the tumour. Mutants with increased motility can invade such polymorphic population and spread within the tumour. While reducing acidity may produce a sudden reduction in tumour proliferation, frequency-dependent selection enables the tumour to adapt to the new conditions and can enable the tumour to restore the original levels of growth and invasiveness.
CONCLUSIONS: The acidity produced by glycolysis acts as a non-linear public good that leads to the coexistence of cells with high and low glycolysis within the tumour. Such heterogeneous population can easily adapt to changes in acidity. Therapies that target acidity can only be effective in the long term if the cost of glycolysis is high, that is, under non-limiting oxygen concentrations. Their efficacy, therefore, is reduced when combined with therapies that impair angiogenesis.
Original languageEnglish
Pages (from-to)259–269
Number of pages11
JournalCell Proliferation
Volume48
Issue number2
Early online date3 Feb 2015
DOIs
Publication statusPublished - Apr 2015

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