Metabolism and its sequelae in cancer evolution and therapy

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. Furthermore, 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, that is, 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 at 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 vis-à-vis respiration, and generation of antioxidants. 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 extracellular pH promotes local invasion, promotes metastasis, and inhibits antitumor immunity. In naturally occurring cancers, low extracellular pH is a strong negative prognostic indicator of metastasis-free survival. Furthermore, it has been shown that inhibition of extracellular acidosis can inhibit metastasis and promote antitumor immunity. Hence, we propose that excess acid production confers a selective advantage for cells during the somatic evolution of cancers.