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Why Do Cancers Have High Aerobic Glycolysis?

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Why Do Cancers Have High Aerobic Glycolysis? REVIEWS 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 reported by Warburg in the 1920s3, leading him to the as occuring by somatic evolution, because it seems for- hypothesis that cancer results from impaired mitochon- mally analogous to Darwinian processes, wherein pheno- drial metabolism. Although the ‘Warburg hypothesis’ typic properties are retained or lost depending on their has proven incorrect, the experimental observations of contribution to individual fitness. According to this increased glycolysis in tumours even in the presence of model, traits that are found in invasive cancers must arise oxygen have been repeatedly verified4. as adaptive mechanisms to environmental proliferative Following Warburg’s initial observation, interest in constraints during carcinogenesis1.Conversely, the com- the metabolic property of cancers has varied over time. mon appearance of a phenotypic property in cancer pop- Intense investigation in the 1960s was followed by a ulations is presumptive evidence that it must confer a steep decline concomitant with the widespread applica- selective growth advantage. tion of newer molecular techniques. The atmosphere of A curious, but common, property of invasive cancers the day was summarized by Sidney Weinhouse, who is altered glucose metabolism. Glycolysis — literally lysis said “Since our perspectives have broadened over the of glucose — first requires the conversion of glucose to years, the burning issues of glycolysis and respiration in pyruvate (FIG. 1) and then to the waste product lactic cancer now flicker only dimly”5. acid. In most mammalian cells, glycolysis is inhibited by However, interest in tumour metabolism has been *Departments of Radiology the presence of oxygen, which allows mitochondria to rekindled, mainly because of the widespread clinical and Applied Mathematics, oxidize pyruvate to CO2 and H2O. This inhibition is application of the imaging technique positron- University of Arizona, termed the ‘Pasteur effect’,after Louis Pasteur, who first emission tomography (PET) using the glucose ana- Tucson, Arizona 85721, USA. 18 6–8 ‡ demonstrated that glucose flux was reduced by the logue tracer fluorodeoxyglucose (FdG) . FdG PET Departments of Radiology 2 and Biochemistry and presence of oxygen .This metabolic versatility of mam- imaging of thousands of oncology patients has Molecular Biophysics, malian cells is essential for maintenance of energy unequivocally shown that most primary and metasta- University of Arizona, production throughout a range of oxygen concentra- tic human cancers show significantly increased glucose Tucson, Arizona 85721, USA. tions. Conversion of glucose to lactic acid in the pres- uptake (FIG. 2).For many cancers, the specificity and Correspondence to R.A.G. e-mail: rgatenby@ ence of oxygen is known as aerobic glycolysis or the sensitivity of FdG PET to identify primary and 9 radiology.arizona.edu ‘Warburg effect’.Increased aerobic glycolysis is uniquely metastatic lesions is near 90% .Sensitivity is lowered doi:10.1038/nrc1478 observed in cancers. This phenomenon was first because FdG PET has difficulty resolving lesions less NATURE REVIEWS | CANCER VOLUME 4 | NOVEMBER 2004 | 891 REVIEWS HEXOKINASES Summary Enzymes that catalyse the transfer of phosphate from ATP •Widespread clinical use of 18fluorodeoxyglucose positron-emission tomography has demonstrated that the glycolytic to glucose to form glucose-6- phenotype is observed in most human cancers. phosphate. This is the first reaction in the metabolism of • The concept of carcinogenesis as a process that occurs by somatic evolution clearly implies that common traits of the glucose and prevents efflux of malignant phenotype, such as upregulation of glycolysis, are the result of active selection processes and must confer a glucose from the cell. significant, identifiable growth advantage. •Constitutive upregulation of glycolysis is likely to be an adaptation to hypoxia that develops as pre-malignant lesions HYPOXIA Refers to a low oxygen level. This grow progressively further from their blood supply. At this stage, the blood supply remains physically separated from means different levels to the growing cells by an intact basement membrane. different investigators, but for •Increased acid production from upregulation of glycolysis results in microenvironmental acidosis and requires further radiation biologists hypoxia adaptation through somatic evolution to phenotypes resistant to acid-induced toxicity. occurs at levels less than 0.1% oxygen in the gas phase. •Cell populations that emerge from this evolutionary sequence have a powerful growth advantage, as they alter their Normoxia refers to normal levels environment through increased glycolysis in a way that is toxic to other phenotypes, but harmless to themselves. The of oxygen (>10%) and anoxia environmental acidosis also facilitates invasion through destruction of adjacent normal populations, degradation of refers to no oxygen. the extracellular matrix and promotion of angiogenesis. •We propose that the glycolytic phenotype, by conferring a powerful growth advantage, is necessary for evolution of invasive human cancers. than 0.8 cm3,and specificity is lowered because other resides at the transport and phosphorylation steps14–16. tissues, notably immune cells, also avidly trap FdG. FdG PET imaging also allows quantitation of glu- When these limitations are accounted for, it can be rea- cose uptake. These studies have consistently correlated sonably surmised that virtually all invasive cancers poor prognosis and increased tumour aggressiveness avidly trap FdG. with increased glucose uptake17,18.In addition, The increased glucose uptake imaged with FdG PET hypoxic tumours, which require increased glycolysis is largely dependent on the rate of glycolysis. FdG to survive, are often19–22,but not always23,more inva- uptake and trapping occurs because of upregulation of sive and metastatic than those with normal oxygen glucose transporters (notably GLUT1 and GLUT3) and levels. These results demonstrate the clinical impor- HEXOKINASES I and II10,11 Although metabolic control over tance of glucose metabolism and have moved the gly- glycolytic rate can be applied at many steps in the gly- colytic phenotype from a laboratory oddity to the colytic pathway12,13,most studies in cancer support the mainstream of clinical oncology. hypothesis that control over glycolytic flux primarily Cells derived from tumours typically maintain their metabolic phenotypes in culture under normoxic condi- tions, indicating that aerobic glycolysis is constitutively upregulated through stable genetic or epigenetic Blood vessel changes. Consistent with the FdG PET results, the gly- colytic rate in cultured cell lines seems to correlate with Glucose HbO2 tumour aggressiveness. For example, non-invasive MCF-7 breast cancer cells have much lower aerobic glucose consumption rates compared with the highly Anion invasive MDA-mb-231 breast cancer cell line (FIG. 3). Glucose O2 exchanger – HCO3 These observations indicate that altered metabo- H+ lism of glucose by tumours is more than a simple Glucose 36 ATP Lactate adaptation to HYPOXIA.We suggest that the near- transporter Mitochondrion universal observation of aerobic glycolysis in invasive Mono- human cancers, its persistence even under normoxic carboxylate H+ conditions and its correlation with tumour aggres- transporter Glucose Lactate siveness indicate that the glycolytic phenotype confers 2 ATP a significant proliferative advantage during somatic Hexokinase evolution of cancer and must, therefore, be a crucial Glucose-6- Pyruvate phosphate component of the malignant phenotype. H+ Sodium–hydrogen At first glance, this hypothesis seems at odds with exchanger an evolutionary model of carcinogenesis, because the proliferative advantage of the glycolytic phenotype is Figure 1 | Glucose metabolism in mammalian cells. Afferent blood delivers glucose and oxygen not immediately apparent. First, anaerobic metabo- (on haemoglobin) to tissues, where it reaches cells by diffusion. Glucose is taken up by specific lism of glucose is inefficient — it produces only 2 ATP transporters, where it is converted first to glucose-6-phosphate by hexokinase and then to per glucose, whereas complete oxidation produces 38 pyruvate, generating 2 ATP per glucose. In the presence of oxygen, pyruvate is oxidized to HCO3, generating 36 additional ATP per glucose. In the absence of oxygen, pyruvate is reduced to lactate, ATP per glucose (FIG. 1).Second, the metabolic prod- which is exported from the cell. Note that both processes
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