Lactate: A Metabolic Driver in the Tumour Landscape

In a tumour environment, lactate is no longer considered as a waste product from fermentative cell metabolism but instead as a powerful molecule that affects the behaviour of each cell surrounding and recruited to the tumour. Lactate establishes metabolic coupling between cancer cells and non-malignant cells, or among cancer cells themselves, thereby sustaining tumour growth. Lactate plays a key role in dampening immunosurveillance mediated by a plethora of immune cells recruited to the tumour site. Environmental lactate triggers signalling activation according to the cell subtype and its specific transporters/receptors. Targeting lactate metabolism and transport is a promising approach for cancer therapeutics. The presence of lactate in human tumours has been long neglected, confined to the role of a waste product derived from glycolysis and as a biomarker of malignancy. More recently, lactate has been rediscovered as signalling molecule that plays important roles in the regulation of the metabolic pathways, the immune response, and cell-to-cell communication within the tumour microenvironment. This review examines recent discoveries about the functional role of lactate in shaping the behaviour and the phenotype of tumour and tumour-associated cells, and describes potential clinical approaches to target lactate transport and metabolism in tumours. The presence of lactate in human tumours has been long neglected, confined to the role of a waste product derived from glycolysis and as a biomarker of malignancy. More recently, lactate has been rediscovered as signalling molecule that plays important roles in the regulation of the metabolic pathways, the immune response, and cell-to-cell communication within the tumour microenvironment. This review examines recent discoveries about the functional role of lactate in shaping the behaviour and the phenotype of tumour and tumour-associated cells, and describes potential clinical approaches to target lactate transport and metabolism in tumours. the dominant stromal cell type in solid tumours, with mesenchyme-like features and the phenotype of activated myofibroblasts. They participate in tumour progression by producing cytokines, chemokines, metabolites, enzymes, and extracellular matrix that sustain the growth of tumour cells. a family of proteins that transport glucose across the plasma membrane. a process in which glutamine is converted into glutamate, then entering the TCA cycle. a family of transcription factors that mediate metabolic and cellular responses to environmental changes such as hypoxia, oxidative stress, and nutrient metabolism. a transcription factor involved in the control of diverse cellular processes, including immune and inflammatory responses, cellular growth, and apoptosis. In the cytoplasm NF-κB binds to the inhibitor IκB in an inactive state; when IκB is phosphorylated and degraded, NF-κB translocates to the nucleus and drives gene expression. a branch from glycolysis – at the first step of glucose metabolism – that is essential for the synthesis of ribonucleotides and NADPH; the latter is required for the free radical scavenging system and is consumed during fatty acid synthesis. a family of iron- and 2-oxoglutarate-dependent dioxygenase enzymes that are involved in cellular adaptation to hypoxia and in the stability of collagen. a type of T cells that participate in the adaptive immune response and that differentiate into different subsets (TH1, TH2, TH17, and regulatory T cells; Tregs) as a function of specific stimuli. a cycle of aerobic reactions that provides energy by the oxidation of acetyl-CoA derived from sugars, lipids, or proteins. non-cancer or stromal cells and the extracellular matrix found in a tumour; the TME mainly comprises CAFs, blood vessels, and immune cells. a metabolic pathway that promotes high exploitation of glucose for rapid energy production and the flow of glycolytic intermediates into collateral pathways to synthesize nucleic acids, amino acids, and lipids, usually culminating in massive lactate production even under normoxic conditions.