Although cancer has historically been viewed as a disorder of proliferation, recent evidence has suggested that it should also be considered a metabolic disease. Growing tumors rewire their metabolic programs to meet and even exceed the bioenergetic and biosynthetic demands of continuous cell growth. The metabolic profile observed in cancer cells often includes increased consumption of glucose and glutamine, increased glycolysis, changes in the use of metabolic enzyme isoforms, and increased secretion of lactate. Oncogenes and tumor suppressors have been discovered to have roles in cancer-associated changes in metabolism as well. The metabolic profile of tumor cells has been suggested to reflect the rapid proliferative rate. Cancer-associated metabolic changes may also reveal the importance of protection against reactive oxygen species or a role for secreted lactate in the tumor microenvironment.
Otto Warburg’s pioneering work in the 1920s established that tumor cells exhibit altered metabolism. Warburg discovered an important distinction between the relative use of different modes of energy production in normal cells and tumors. In normal tissues, most of the pyruvate formed from glycolysis enters the tricarboxylic acid (TCA) cycle and is oxidized via oxidative phosphorylation. In tumors, in contrast, the pyruvate is largely converted to lactic acid and energy is produced anaerobically. This finding seemed counterintuitive. Surely, a rapidly proliferating cancer cell would prefer the 36 ATPs that can be claimed by complete oxidation of a glucose molecule to the two ATPs available through glycolysis. Furthermore, this shift in metabolism in which pyruvate is converted to lactate and secreted, rather than being oxidized, occurred in tumors even when there was sufficient oxygen to support mitochondrial function. The conversion of most pyruvate to lactate through fermentation, even when oxygen is present, is called aerobic glycolysis or the Warburg effect.