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WHY DO CANCERS HAVE HIGH AEROBIC GLYCOLYSIS?
Robert A. Gatenby* and Robert J. Gillies
Abstract | If carcinogenesis occurs by somatic evolution, then common components of the cancer phenotype result from active selection and must, therefore, confer a significant growth advantage. A near-universal property of primary and metastatic cancers is upregulation of glycolysis, resulting in increased glucose consumption, which can be observed with clinical tumour imaging. We propose that persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions. However, upregulation of glycolysis leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity. Subsequent cell populations with upregulated glycolysis and acid resistance have a powerful growth advantage, which promotes unconstrained proliferation and invasion.
The multistep process of carcinogenesis is often described as occuring by somatic evolution, because it seems formally analogous to Darwinian processes, wherein phenotypic properties are retained or lost depending on their contribution to individual fitness. According to this model, traits that are found in invasive cancers must arise as adaptive mechanisms to environmental proliferative constraints during carcinogenesis1.Conversely, the common appearance of a phenotypic property in cancer populations is presumptive evidence that it must confer a selective growth advantage.
A curious, but common, property of invasive cancers is altered glucose metabolism. Glycolysis literally lysis of glucose first requires the conversion of glucose to pyruvate (FIG. 1) and then to the waste product lactic acid. In most mammalian cells, glycolysis is inhibited by the presence of oxygen, which allows mitochondria to oxidize pyruvate to CO2 and H2O. This inhibition is termed the Pasteur effect, after Louis Pasteur, who first demonstrated that glucose flux was reduced by the presence of oxygen2.This metabolic versatility of mammalian cells is essential for maintenance of energy production throughout a range of oxygen concentrations. Conversion of glucose to lactic acid in the presence of oxygen is known as aerobic glycolysis or the Warburg effect. Increased aerobic glycolysis is uniquely observed in cancers. This phenomenon was first
reported by Warburg in the 1920s3, leading him to the hypothesis that cancer results from impaired mitochondrial metabolism. Although the Warburg hypothesis has proven incorrect, the experimental observations of increased glycolysis in tumours even in the presence of oxygen have...