Heterogeneity and proliferation of invasive cancer subclones in game theory models of the Warburg effect.
Heterogeneity and proliferation of invasive cancer subclones in game theory models of the Warburg effect.
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DOI：
10.1111/cpr.12169
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发表时间：
2015-04
影响因子：
8.5
通讯作者：
Archetti M
中科院分区：
文献类型：
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作者：
Archetti M
瓦尔堡效应是从有氧能量产生到无氧糖酵解的转换，通过诱导肿瘤微环境的酸化来促进肿瘤增殖和运动。降低酸度的疗法可能会削弱肿瘤的生长和侵袭性。我分析了在瓦尔堡效应下，细胞增殖的动力学和对针对酸性的治疗的抵抗力。在进化博弈论的框架下，在具有集体互动的多玩家博弈中评估了具有增加的糖酵解和运动性的突变细胞的动力学。微环境中酸度水平的扰动已被用于模拟靶向糖酵解的治疗效果。糖酵解的非线性效应诱导频率依赖性克隆选择，导致糖酵解细胞和非糖酵解细胞在肿瘤内共存。具有增加的运动性的突变体可以侵入这样的多态性群体并在肿瘤内扩散。虽然降低酸度可能会导致肿瘤细胞增殖的突然减少，但频率依赖性选择使其能够适应新的条件，并使肿瘤能够恢复其原始的生长和侵袭水平。糖酵解产生的酸度作为一种非线性公共产品，导致肿瘤内糖酵解水平高和低的细胞共存。这样的异质种群很容易适应酸度的变化。如果糖酵解的成本很高，即在非限制性氧浓度下，靶向酸度的治疗方法才能长期有效。因此，当与损害血管生成的疗法组合时，它们的功效降低。
The Warburg effect, a 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 analysed the dynamics of cell proliferation and of resistance to therapies that target acidity, in a population of cells, under the Warburg effect. The dynamics of mutant cells with increased glycolysis and motility has been assessed in a multi‐player game with collective interactions in the framework of evolutionary game theory. Perturbations of the level of acidity in the microenvironment have been used to simulate the effect of therapies that target glycolysis. The non‐linear effects of glycolysis induce frequency‐dependent clonal selection leading to coexistence of glycolytic and non‐glycolytic cells within a tumour. Mutants with increased motility can invade such a polymorphic population and spread within the tumour. While reducing acidity may produce a sudden reduction in tumour cell proliferation, frequency‐dependent selection enables it to adapt to the new conditions and can enable the tumour to restore its original levels of growth and invasiveness. The acidity produced by glycolysis acts as a non‐linear public good that leads to coexistence of cells with high and low glycolysis within the tumour. Such a 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.