Episodic, transient systemic acidosis delays evolution of the malignant phenotype: Possible mechanism for cancer prevention by increased physical activity

Abstract

Background: The transition from premalignant to invasive tumour growth is a prolonged multistep process governed by phenotypic adaptation to changing microenvironmental selection pressures. Cancer prevention strategies are required to interrupt or delay somatic evolution of the malignant invasive phenotype. Empirical studies have consistently demonstrated that increased physical activity is highly effective in reducing the risk of breast cancer but the mechanism is unknown.

Results: Here we propose the hypothesis that exercise-induced transient systemic acidosis will alter the in situ tumour microenvironment and delay tumour adaptation to regional hypoxia and acidosis in the later stages of carcinogenesis. We test this hypothesis using a hybrid cellular automaton approach. This model has been previously applied to somatic evolution on epithelial surfaces and demonstrated three phases of somatic evolution, with cancer cells escaping in turn from the constraints of limited space, nutrient supply and waste removal. In this paper we extend the model to test our hypothesis that transient systemic acidosis is sufficient to arrest, or at least delay, transition from in situ to invasive cancer.

Conclusions: Model simulations demonstrate that repeated episodes of transient systemic acidosis will interrupt critical evolutionary steps in the later stages of carcinogenesis resulting in substantial delay in the evolution to the invasive phenotype. Our results suggest transient systemic acidosis may mediate the observed reduction in cancer risk associated with increased physical activity.

Figure 1

Automaton evolution. (Reproduced from [17].) The temporal evolution of a typical cellular automaton after (a) t = 0, (b) t = 100, (c) t = 250 and (d) t = 300 generations. Shown are normal epithelial (grey), hyperplastic (pink), hyperplastic-glycolytic (green) and hyperplastic-glycolytic-acid-resistant (yellow) cells. Cells with other phenotypic patterns are shown as black.

Figure 2

Effect of sustained acidosis. (a) Variation in the development rate R with serum acid level h_X (plotted on a log scale). Each data point is the mean value of R calculated over 50 simulations, whilst the accompanying error bars show the standard errors of these means. (b) Variation in epithelium survival with h_X.

Figure 3

Effect of transient acidosis. (a) Variation in the development rate R with proportion of time under exercise. Exercise is assumed to correspond to high acidity (h_X = 400), whilst during rest acidity drops to normal levels (h_X = 0). (b) Variation in epithelium survival with exercise time.