Cancer metabolism as a therapeutic target: finding the right target(s) in the context of tumor heterogeneity, evolution, and metabolic plasticity.

“Cancer, above all other diseases, has countless secondary causes. But, even for cancer, there is only one prime cause. Summarized in a few words, the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar. All normal body cells are thus obligate aerobes, whereas all cancer cells are partial anaerobes.” This is how Otto Warburg, at a 1966 meeting of Nobel laureates, described his theory on the origin of cancer as a metabolic disease.[1] The theory was based on the observation that, unlike the majority of normal cells, tumor cells derive energy via biochemical reactions characteristic “of the lowest living forms,” and which consist of the nonoxidative catabolism of glucose (glycolysis), the production of pyruvate, and the subsequent conversion of pyruvate to lactic acid. This biochemical process, named anaerobic respiration, or fermentation, generates several end products, including lactic acid itself, which are now known to contribute to various aspects of tumor progression.