LAUSR

Human clear cell renal cell carcinoma (ccRCC) tumours display extensive metabolic alterations, mainly driven by the pseudo-hypoxic state associated with loss of the VHL (von Hippel–Lindau) tumour suppressor gene — the principal genetic cause of ccRCC. Although mechanistic and metabolomic studies had already suggested that ccRCC cells produce energy mainly from aerobic glycolysis, also termed the Warburg effect, isotope tracing studies recently published in Cell Press represent the first convincing in vivo evidence of this effect in human tumours. Courtney et al. show that glycolysis is increased and glucose oxidation is suppressed, a phenotype consistent with the Warburg effect, in ccRCC tumours compared with matched adjacent healthy kidney tissue. The researchers administered 13C-glucose (in which all six carbon atoms were substituted with 13C) to five patients with ccRCC who were undergoing nephrectomy or partial nephrectomy (this infusion increased the patients’ plasma glucose levels by 30–50%). The presence of this isotope in metabolites was traced by proton-decoupled 13C-NMR, with values normalized to the patients’ steady-state plasma 13C-glucose levels. The ccRCC tumours exhibited minimal glucose oxidation and minimal activity of the tricarboxylic acid (TCA) cycle. Moreover, the alterations in levels of TCA cycle intermediates were consistent with decreased activity of pyruvate dehydrogenase, a key enzyme controlling entry into the TCA cycle. Interestingly, although the Warburg effect was initially hypothesized to be common to all aggressive tumours, Courtney et al. also report that ccRCC tumours seem to rely more heavily on aerobic glycolysis than do brain or lung tumours — in which similar isotope tracing studies found surprisingly high levels of oxidation of glucose and other fuels, despite evidence of aerobic glycolysis. These observations further highlight the distinctive metabolic profile of ccRCC tumours. Caroline Barranco K I D N E Y C A N C E R