Lactate in the Tumor Microenvironment: An Essential Molecule in Cancer Progression and Treatment

Abstract

Cancer is a complex disease that includes the reprogramming of metabolic pathways by malignant proliferating cells, including those affecting the tumor microenvironment (TME). The “TME concept” was introduced in recognition of the roles played by factors other than tumor cells in cancer progression. In response to the hypoxic or semi-hypoxic characteristic of the TME, cancer cells generate a large amount of lactate via the metabolism of glucose and glutamine. Export of this newly generated lactate by the tumor cells together with H+ prevents intracellular acidification but acidifies the TME. In recent years, the importance of lactate and acidosis in carcinogenesis has gained increasing attention, including the role of lactate as a tumor-promoting metabolite. Here we review the existing literature on lactate metabolism in tumor cells and the ability of extracellular lactate to direct the metabolic reprogramming of those cells. Studies demonstrating the roles of lactate in biological processes that drive or sustain carcinogenesis (tumor promotion, angiogenesis, metastasis and tumor resistance) and lactate’s role as an immunosuppressor that contributes to tumor evasion are also considered. Finally, we consider recent therapeutic efforts using available drugs directed at and interfering with lactate production and transport in cancer treatment.

The Effect of Hypoxia on the Expression of CXC Chemokines and CXC Chemokine Receptors—A Review of Literature

“…It also protects cancer cells by impairing the function of NK cells [ 64 , 65 ] and increasing the production of immunosuppressive proteins such as indoleamine 2,3-dioxygenase (IDO), human leukocyte antigen-G (HLA-G), programmed death-ligand 1 (PD-L1) and metabolites such as adenosine [ 66 , 67 ]. The hypoxia-induced acidosis of the cancer microenvironment, which is caused by an increased production and secretion of lactate is also important [ 66 , 68 ]. Lactate causes tumor immune evasion and neoplastic cell migration.…”

Postbiotics, Metabolic Signaling, and Cancer

“…The endogenously produced lactate in the established tumors has been identified as a driver of angiogenesis, immune evasion, metastasis, and resistance to therapy [ 106 ]. On the other hand, lactate delivered by postbiotic supplementation may serve as an inhibitor of carcinogenesis through the maintenance of the epithelial integrity and downregulation of the tissue inflammation [ 11 , 107 , 108 , 109 , 110 , 111 ].…”

The Importance of Mitochondrial Pyruvate Carrier in Cancer Cell Metabolism and Tumorigenesis

“…Tumor cells, moreover, need to maintain a relatively alkaline intracellular pH for optimal metabolic enzyme activity (reviewed in [ 151 ]). As a result, lactic acid concentration, which in normal tissues ranges from 1.5 to 3 mM, can be as high as 40 mM in the TME, whereas the pH of tumors can be as low as 5.6 compared to 7.4 for normal tissues [ 152 ]. The H + /Na + -exchanger NHE1 and the monocarboxylate transporters (MCT) are key molecules in these respects.…”

“…Lactic acid and acidosis can have a negative impact on the activity of anti-tumor cells. It is well described that lactate concentrations over 20 mM cause apoptosis in T lymphocytes, NK, and NKT cells [ 152 ]. NK cell cytolytic activity is also negatively regulated by reducing their expression of activation receptor NKp46 and by inhibiting the production of perforin and granzyme B [ 174 ].…”