The Warburg Effect, Lactate, and Nearly a Century of Trying to Cure Cancer

Nearly 100 years ago, Otto Warburg undertook a study of tumor metabolism, and discovered increased lactate caused by increased glycolysis in cancer cells. His experiments were conducted in the presence of excess oxygen, but today tumor tissue is known to be a hypoxic environment. However, an increase of glycolysis and lactate production is still a valid observation. Numerous abnormalities and mutations of metabolic enzymes have been found in many cancers. For example, pyruvate kinase M2 has been associated with many cancers and is a major contributor to directing glycolysis into fermentation, forming lactate. Increases in several enzymes, including glucose 6-phosphate dehydrogenase, pyruvate kinase M2, Rad6, or deficiency of other enzymes such as succinate dehydrogenase, all may contribute directly or indirectly to increases in lactate associated with the Warburg effect. In addition, the increased lactate and acid-base changes are modified further by monocarboxylate transporters and carbonic anhydrase, which contribute to alkalinizing tumor cells while acidifying the tumor extracellular environment. This acidification leads to cancer spread. Fully understanding the mechanisms underlying the Warburg effect should provide new approaches to cancer treatment. (C) 2019 Elsevier Inc. All rights reserved.