Fig. 2.

The different roles of cancer-generated lactic acid in promoting tumour growth and metastasis. Enhanced glycolysis and glutaminolysis generate large amounts of lactic acid that is exported by monocarboxylate transporters (MCT) 1 and 4. The accumulation of lactic acid in the extracellular milieu induces drop in extracellular pH (pHe), acidification of tumour microenvironment and promotes several cancer processes leading to cell survival, tumour growth and metastasis. Lactic acid stimulates angiogenesis by increasing the production of the vascular endothelial growth factor (VEGF) and its receptor VEGFR2 by tumour and endothelial cells. Lactate drives also angiogenesis through the activation of hypoxia-inducible factor 1 (HIF-1), N-Myc downstream-regulated gene 3 (NDRG3) protein and the stimulation of the production of interleukin 8 (IL8). Increased extracellular lactate levels influence cancer cell motility by promoting hyaluronan production, which acts on fibroblasts and cancer cell cytoskeleton through interaction with CD44. More importantly, lactate generated by altered cancer metabolism plays an important role in escape of immune surveillance, mostly through decreased cytotoxic activity of human T lymphocytes (T cells) [75, 76] and natural killer (NK) cells. Further, lactate reduces dendritic cell maturation, induces the accumulation of myeloid derived suppressor cells, and promotes M2-like polarisation of tumour-associated macrophages