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

Smallbone K, Maini PK, Gatenby RA - Biol. Direct (2010)

Bottom Line: The transition from premalignant to invasive tumour growth is a prolonged multistep process governed by phenotypic adaptation to changing microenvironmental selection pressures.Empirical studies have consistently demonstrated that increased physical activity is highly effective in reducing the risk of breast cancer but the mechanism is unknown.We test this hypothesis using a hybrid cellular automaton approach.

View Article: PubMed Central - HTML - PubMed

Affiliation: Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, 131 Princess Street, Manchester, M1 7DN, UK. kieran.smallbone@manchester.ac.uk

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.

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Effect of sustained acidosis. (a) Variation in the development rate R with serum acid level hX (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 hX.
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Figure 2: Effect of sustained acidosis. (a) Variation in the development rate R with serum acid level hX (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 hX.

Mentions: In Fig. 2(a) we see how the development rate R varies with changes in serum acidity hX. We vary the external acid levels from hX = 0 (normal) to hX ~1000, equivalent to pH 6.8, corresponding to the threshold for normal cell survival [16]. Decreases in pHe of this magnitude have been observed in various human cancers [18]. Note that a log scale is used. Development rate R remains fairly constant until h ~ 100 (a drop of around 0.1 pH units), when a marked decrease is observed. Looking further however, we see (Fig. 2(b)) that this result follows simply because the harsher conditions lead to death of the entire epithelium; normal cells die out before having the opportunity to turn cancerous.


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

Smallbone K, Maini PK, Gatenby RA - Biol. Direct (2010)

Effect of sustained acidosis. (a) Variation in the development rate R with serum acid level hX (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 hX.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2864239&req=5

Figure 2: Effect of sustained acidosis. (a) Variation in the development rate R with serum acid level hX (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 hX.
Mentions: In Fig. 2(a) we see how the development rate R varies with changes in serum acidity hX. We vary the external acid levels from hX = 0 (normal) to hX ~1000, equivalent to pH 6.8, corresponding to the threshold for normal cell survival [16]. Decreases in pHe of this magnitude have been observed in various human cancers [18]. Note that a log scale is used. Development rate R remains fairly constant until h ~ 100 (a drop of around 0.1 pH units), when a marked decrease is observed. Looking further however, we see (Fig. 2(b)) that this result follows simply because the harsher conditions lead to death of the entire epithelium; normal cells die out before having the opportunity to turn cancerous.

Bottom Line: The transition from premalignant to invasive tumour growth is a prolonged multistep process governed by phenotypic adaptation to changing microenvironmental selection pressures.Empirical studies have consistently demonstrated that increased physical activity is highly effective in reducing the risk of breast cancer but the mechanism is unknown.We test this hypothesis using a hybrid cellular automaton approach.

View Article: PubMed Central - HTML - PubMed

Affiliation: Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, 131 Princess Street, Manchester, M1 7DN, UK. kieran.smallbone@manchester.ac.uk

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.

Show MeSH
Related in: MedlinePlus