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

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.

Moonlight functions of glycolytic enzymes in cancer

“…Therefore, the Warburg effect observed in many cancers and emerging in glycolysis intensification and hyperexpression of glycolytic enzymes may have a crucial meaning for glycolytic enzymes moonlighting. Increased lactate production as well as acidification of the microenvironment and other metabolic changes that occurred during tumour growth ( Shegay et al, 2022 ) may induce functional switching of glycolytic enzymes to stimulate their moonlighting. Due to moonlight action, the proteins will induce their own expression, promote tumour cell transformation to a stemlike phenotype, and stimulate their proliferation, invasion, migration, and resistance to therapy agents.…”

Mitochondria: It is all about energy

“…Other studies showed that cancer develops when “cancerous” mitochondria are implanted in a healthy cell without any genetic mutations ( Gyamfi et al, 2022 ). Many oncometabolites causing mitochondrial disorders and possibly initiating the cancer process have been identified, and as aforementioned, lactate is one of the most ubiquitous oncometabolites in cancer ( Kes et al, 2020 ; Shegay et al, 2022 ). Aerobic glycolysis in tumor cells is important, but dynamic adjustment of mitochondrial RNA modification directly contributes to tumor malignancy and metastasis, shaping tumor metabolic plasticity ( Delaunay et al, 2022 ).…”

Cellular Adaptation Takes Advantage of Atavistic Regression Programs during Carcinogenesis

“…In the light of the atavistic theory, the role of lactate in cancer transformation has been reconsidered [84,85]. Indeed, lactate causes acidification of the TME (as a consequence of the hypoxic state), suppresses antitumor immunity, fuels cell proliferation, and promotes angiogenesis during tumor growth, but also stimulates cell migration, metastasis, and release of tumor exosomes.…”

“…In fact, we recently hypothesized that lactic acid fermentation could be considered a maladaptive mechanism and an evolutionary regression promoting drug resistance [39]. Furthermore, alterations in the TME can promote the formation of other oncogenic metabolites and induce protein modifications at the post-translational level, facilitating cellular adaptation to new environments [84,85]. Hence, targeting lactate production and transport may represent a promising approach for cancer therapy [39,86].…”