Aerobic glycolysis in cancers: Implications for the usability of oxygen‐responsive genes and fluorodeoxyglucose‐PET as markers of tissue hypoxia

Abstract

The hypoxia-responsiveness of the glycolytic machinery may allow pretreatment identification of hypoxic tumors from HIF-1 targets (e.g., Glut-1) or [18F]-fluorodeoxyglucose positron emission tomography but results have been mixed. We hypothesized that this discrepancy is an inevitable consequence of elevated aerobic glycolysis in tumors (Warburg effect) as energetics in predominantly glycolytic cells is little affected by hypoxia. Accordingly, we characterized glycolytic and mitochondrial ATP generation in normoxic and anoxic cell lines. Measurements demonstrated that most cancer cells rely largely on aerobic glycolysis as it accounts for 56-63% of their ATP budget, but in the cervical carcinoma SiHa, ATP synthesis was mainly mitochondrial. Moreover, the stimulatory effect of anoxia on glycolytic flux was inversely correlated to the relative reliance on aerobic glycolysis. Next, tumor cells representing a Warburg or a nonglycolytic phenotype were grown in mice and spatial patterns of hypoxia (pimonidazolestained), Glut-1 expression and 18 F-FDG uptake were analysed on sectioned tumors. Only in SiHa tumors did foci of elevated glucose metabolism consistently colocalize with regions of hypoxia and elevated Glut-1 expression. In contrast, spatial patterns of Glut-1 and pimonidazole staining correlated reasonably well in all tumors. In conclusion, Glut-1's value as a hypoxia marker is not severely restricted by aerobic glycolysis. In contrast, the specificity of 18 F-FDG uptake and Glut-1 expression as markers of regional hypoxia and glucose metabolism, respectively, scales inversely with the intensity of the Warburg effect. This linkage suggests that multi-tracer imaging combining FDG and hypoxia-specific markers may provide therapeutically relevant information on tumor energetic phenotypes. ' 2008 Wiley-Liss, Inc.Key words: hypoxia; Warburg; Pasteur; fluorodeoxyglucose; Glut-1 German biologist Otto Warburg 1 changed our understanding of tumor energy metabolism, by demonstrating that cancer cells deviate from their nontransformed counterparts by a vigorous formation of lactate even in the presence of oxygen (i.e., aerobic glycolysis). Mitochondrial defects are widespread in cancers and Warburg rationally hypothesized that impaired respiratory capacity leads to a compensatory increase in glycolysis. However, the cause and effect relationship between the oxidative phosphorylation (OXPHOS) and aerobic glycolysis is unclear, as at least some cancer cell lines are able to increase oxygen consumption rate (OCR) when glycolysis is inhibited or when treated with mitochondrial uncouplers. 2,3 Cancer cell energy metabolism has received renewed interest recently, when some common oncogenic mutations have been directly linked to the glycolytic phenotype, 4,5 but tumor hypoxia is common, and the imposed ATP deficit could be an important trigger of high glucose consumption in vivo (Pasteur effect).Tumor hypoxia, in particular in squamous cell carcinomas (SCCs), adversely affects prognosis by enhancing resistance to radio-and ch...

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