Evolutionary View on Lactate-Dependent Mechanisms of Maintaining Cancer Cell Stemness and Reprimitivization

SIMPLE SUMMARY: For a long-time lactic acid has been considered as a toxic end-product of metabolism that cause different adverse effects. However, in recent decades a plenty of studies has refuted this suggestion and revealed many functions of lactate in living organisms. Lactic acid may be considered as one of the most ancient metabolites with signaling function and high regulatory activity. Lactate regulates key metabolic processes such as proteins expression, cells’ differentiation, inflammatory response, as well as provides stemness and unlimited cell growth, which is used by malignant tumors for their growth. Although lactatemia, observed in many cancer diseases, is possibly associated with the activation of ancient evolutionary defense mechanisms, aimed at combating metabolic disorders, and which tumors began to use for their own purposes – the acquisition of stem properties, rapid proliferation, and metastasis. In our review we aimed to summarize the accumulated knowledge about the functions of lactate in the process of carcinogenesis and to consider the possible evolutionary significance of the Warburg effect. ABSTRACT: The role of lactic acid (lactate) in cell metabolism has been significantly revised in recent decades. Initially, lactic acid was attributed to the role of a toxic end-product of metabolism, with its accumulation in the cell and extracellular space leading to acidosis, muscle pain, and other adverse effects. However, it has now become obvious that lactate is not only a universal fuel molecule and the main substrate for gluconeogenesis but also one of the most ancient metabolites, with a signaling function that has a wide range of regulatory activity. The Warburg effect, described 100 years ago (the intensification of glycolysis associated with high lactate production), which is characteristic of many malignant tumors, confirms the key role of lactate not only in physiological conditions but also in pathologies. The study of lactate’s role in the malignant transformation becomes more relevant in the light of the “atavistic theory of carcinogenesis,” which suggests that tumor cells return to a more primitive hereditary phenotype during microevolution. In this review, we attempt to summarize the accumulated knowledge about the functions of lactate in cell metabolism and its role in the process of carcinogenesis and to consider the possible evolutionary significance of the Warburg effect.