Lactate Beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy

Abstract

To sustain their high proliferation rates, most cancer cells rely on glycolytic metabolism, with production of lactic acid. For many years, lactate was seen as a metabolic waste of glycolytic metabolism; however, recent evidence has revealed new roles of lactate in the tumor microenvironment, either as metabolic fuel or as a signaling molecule. Lactate plays a key role in the different models of metabolic crosstalk proposed in malignant tumors: among cancer cells displaying complementary metabolic phenotypes and between cancer cells and other tumor microenvironment associated cells, including endothelial cells, fibroblasts, and diverse immune cells. This cell metabolic symbiosis/slavery supports several cancer aggressiveness features, including increased angiogenesis, immunological escape, invasion, metastasis, and resistance to therapy. Lactate transport is mediated by the monocarboxylate transporter (MCT) family, while another large family of G protein-coupled receptors (GPCRs), not yet fully characterized in the cancer context, is involved in lactate/acidosis signaling. In this mini-review, we will focus on the role of lactate in the tumor microenvironment, from metabolic affairs to signaling, including the function of lactate in the cancer-cancer and cancer-stromal shuttles, as well as a signaling oncometabolite. We will also review the prognostic value of lactate metabolism and therapeutic approaches designed to target lactate production and transport.

SLC6A14 and SLC38A5 Drive the Glutaminolysis and Serine–Glycine–One-Carbon Pathways in Cancer

“…Thus, in cancer cells, glucose gets converted partly into CO 2 but mostly into lactic acid, consequently resulting in increased levels of lactate outside in the tumor microenvironment. Recent studies have shown that this extracellular lactate participates in promoting cancer cell survival and proliferation by multiple autocrine and paracrine mechanisms via the cell-surface receptor GPR81 (HCAR1 or hydroxycarboxylic acid receptor 1) [ 11 , 12 ]. Another important aspect of the increased rate of glycolysis in cancer cells is the elevated levels of glycolytic intermediates, which can feed into metabolic pathways that provide additional support to cancer cell proliferation.…”

Another Consequence of the Warburg Effect? Metabolic Regulation of Na+/H+ Exchangers May Link Aerobic Glycolysis to Cell Growth

“…Increased glucose uptake and metabolism to fuel aerobic glycolysis is also a general feature of mitogenic stimulation under physiological conditions and oncogenic transformation [ Figure 1B and Refs. ( 67 – 69 )] and is generally referred to as the Warburg effect. Although it was originally assumed that tumor cells upregulate glycolysis even in the presence of oxygen due to defective mitochondria, it is now clear that increased rates of glycolysis allow the redirection of metabolic fluxes toward more efficient biomass production ( 69 , 70 ) in actively proliferating cells and form the molecular basis of using PET scans for tumor detection ( 71 ).…”

DRP1 promotes lactate utilization in KRAS‐mutant non‐small‐cell lung cancer cells

“…Lactate, once considered a dead‐end product of glycolysis, is emerging as an essential regulator of multiple biological processes, including tumor metabolism, the immune response, and signal transduction 23,33 . Increased lactate uptake is a characteristic of lung cancer metabolism 5 .…”