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Metabolism and Its Sequelae in Cancer Evolution and Therapy #MMPMID25815848
Gillies RJ; Gatenby RA
Cancer J 2015[Mar]; 21 (2): 88-96 PMID25815848show ga
Cancers progress through a series of events that can be characterized as ?somatic evolution?. A central premise of Darwinian evolutionary theory is that the environment imparts pressure to select for species that are most fit within that particular microenvironmental context. Further, the rate of evolution is proportional to both 1) the strength of the environmental selection and 2) the phenotypic variance of the selected population. It is notable that, during the progression of cancers from carcinogenesis to local invasion to metastasis, the selective landscape continuously changes and throughout this process there is increased selection for cells that have altered metabolic phenotypes: implying that these phenotypes impart a selective advantage during the process of environmental selection. One of the most prevalent selected phenotypes is that of aerobic glycolysis, i.e. the continued fermentation of glucose even in the presence of adequate oxygen. The mechanisms of this so-called ?Warburg Effect? have been well studied and there are multiple models to explain how this occurs and the molecular level. Herein, we propose that unifying insights can be gained by evaluating the environmental context within which this phenotype arises. In other words, we focus not on the ?how?, but the ?why? do cancer cells exhibit high aerobic glycolysis. This is best approached by examining the sequelae of aerobic glycolysis that may impart a selective advantage. Many of these have been considered, including: generation of anabolic substrates, response rates of glycolysis via-a-vis respiration, and generation of anti-oxidants. A further sequeala considered here is that aerobic glycolysis results in a high rate of lactic acid production; resulting in acidification of the extracellular space. Indeed, it has been shown that a low pHe promotes local invasion, promotes metastasis and inhibits anti-tumor immunity. In naturally occurring cancers, low pHe is a strong negative prognostic indicator of metastasis free survival. Further, it has been shown that inhibition of extracellular acidosis can inhibit metastasis and promote anti-tumor immunity. Hence, we propose that excess acid production confers a selective advantage for cells during the somatic evolution of cancers.
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Cancer+J 2015 ; 21 (2): 88-96
