Described by Otto Warburg a century ago, accelerated glucose consumption and lactate production under fully aerobic conditions is ubiquitous in solid cancers. Observations of accelerated glucose uptake and lactate secretion under fully aerobic conditions led Warburg to posit that cancer could be attributed to an injury to the cellular respiratory system (mitochondria). Still, for many decades lactate was considered a “waste” product resulting from lack of oxygen. However, pioneering work and discoveries by George Brooks since the 1980’s have demonstrated that lactate is the preferred fuel for most cells, the main gluconeogenic precursor in the body, and a signaling molecule (a “lactormone” and “myokine”) capable of inducing gene expression. In concert, Zhang et al. have reported recently, that the key role of lactate in histone acetylation (“lactylation”) is the acetylation of lysine histone residues, acting as an epigenetic modulator and increasing gene transcription.
In 2017, scientists San-Millan and Brooks developed the “lactagenesis hypothesis” by which we posited that accelerated lactate production in tumors was not for bioenergetics, but rather owing to its powerful signaling properties, the role of lactate in tumors was to stimulate carcinogenesis. Posteriorly, in 2019 they demonstrated that lactate functions as an “oncometabolite” and regulates the expression of major genes related to carcinogenesis in MCF7 breast cancer cells. Now, the same team demonstrated that both estrogen-positive (ER+) MCF7 breast cancer cells and triple-negative MDA-MB-231 breast cancer cells (TNBC) use lactate as fuel and driver of gene expression. However the effects have been different, thought an interesting finding is that lactate enhanced the epitelial-mesenchimal transition (EMT), a phenomenon linked to cell immaturity and tissue invasion (metastasis).
Endogenous lactate regulates the expression of multiple genes involved in carcinogenesis. In MCF7 cells, lactate increased the expression of growth factors (EGFR, VEGF) and mitogenic signaling components (KRAS, mTOR, PIK3CA, TP53 and CDK4); while decreased the expression of regulators of DNA repair and genomic stability (ATM, BRCA1, BRCA2, E2F1, MYC) mainly at 48h of exposure. On the other hand, in the MDA-MB-231 cell line, lactate slightly changed the composition, enhancing ATM and E2F1 (repressed in MCF7 cells), while repressing CDK4 and CDK6 cell cyle kinases (enhanced in MCF7 cells). Finally, lactate decreased E-cadherin protein expression in MCF7 cells and increased vimentin expression in MDA-MB-231 cells. Both these proteins are involved in cell motility and, in general, MCF7 cells are characterized by an epithelial phenotype, while MDA-MB-231 a mesenchymal one.
This could explain the effect of lactate on the phenotype of thiese cancer cells. TNBC cells possess significantly higher amount of vimentin than ER+ cancer cells, which could explain their higher eggressivity compared to the latter. Importantly, we found that lactate elicits overexpression of a key tumor suppressor gene, TP53 in both cancer cell lines. Although P53 is typically considered a “tumor suppressor” protein that binds to and repairs damaged DNA or signals for apoptosis in irreparable cells, missense mutations in TP53 elicit mutant p53 proteins with potential gain-of-function properties that stimulate tumor cell proliferation, migration, invasion, survival, chemoresistance, cancer metabolism, and/or tissue architecture disruption. Consequently, overexpression of P53 may be associated with increased mortality and poor prognosis, especially for the triple negative breast cancer, though ER+ tumors may sometime be aggressive as well.
In conclusion, lactate is just not a “waste” or “junk disposable” molecule that cancer cells produce from their metabolism. Considered its more and more important “gamekeeping” role, scientists deem that blocking cellular lactate production as well as the exchange between cancer cells and surrounding stroma cells, affecting the tumor microenvironment, should be a priority in cancer research.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
San-Millan I et al. bioRxiv 2023 Mar 23: 533060.
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San-Millan I, Brooks GA. Carcinogenesis 2017; 38(2):119.