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    • Although resembling a differential symbiotic relationship in

    2021-10-16

    Although resembling a differential symbiotic relationship, interplay between prostate tumour CAFs promotes PKM2/HIF-1-driven transcriptional regulation in prostate cancer cells that exploit lactate produced by CAFs and undergo epithelial-to-mesenchymal transition (EMT) [21]. Although recent observations reveal that the CAF secretome (plausibly also lactate) stimulates reversible variations in the pattern of DNA methylation that are necessary for EMT in androgen-independent prostate carcinoma cells [45], the involvement of lactate in modifying tumour epigenetics (e.g., methylation) has not yet been established. However, lactate has been shown to inhibit NAD+-independent histone deacetylases, with a conceivable impact on fine-tuning the regulation of gene transcription, although a specific role of lactate in tumour epigenetics remains unknown [46]. As previously described, cancer immune evasion has been recognized, at least in part, as a ‘lactate-affair’ (Figure 2). In addition to the metabolic role of lactate, a signalling role has also emerged for lactate in driving cancer immune evasion. For instance, cytotoxic T cell effector functions are impaired because lactic bace inhibitor interferes with T cell receptor-triggered phosphorylation and activation of the p38 and JNK/c-Jun signalling pathways, leading to blockade of IFN-γ production [47]. In addition, lactate acts as a proinflammatory mediator by promoting IL23 transcription in Toll-like receptor (TLR)-stimulated monocytes/macrophages, that sustains IL-23-dependent secretion of IL-17, polarizing immune responses toward a TH17 profile [48]. In tumour-associated macrophages, lactate upload also drives HIF-1-dependent transcription of the genes encoding VEGF and the arginine-metabolizing enzyme arginase 1 (ARG1), driving their polarization toward an M2-phenotype [25], although others have proposed a lactate-dependent activation of ERK/STAT3 signalling [49]. In addition to its negative effects on effector T cells, tumour-derived lactate stimulates naïve T cells to undergo apoptosis as a result of loss of FAK family-interacting protein FIP200, resulting in autophagy impairment and oxidative stress. A reduction in lactate-induced NAD+ levels is crucial for regulating adenylate/uridylate-rich elements in Fip200 mRNA, leading to reduced FIP200 expression [50]. Beyond its role as an intracellular signalling mediator, lactate can also act as an extracellular ligand. G protein-coupled receptor 81 (GPR81, also known as HCAR1) is a Gi-coupled receptor for lactate that is expressed by adipocytes and meningeal fibroblasts, where it reduces lipolysis by lowering cAMP levels [51] and induces brain vascularization via ERK1/2 and Akt signalling [52]. GPR81 is also expressed in different tumour cells, where its activation finely tunes the lactate-sensitive machinery (by modulating the expression of MCTs, CD147, and PGC1α), thereby sustaining tumour growth and metastasis [53]. The lactate/GPR81 pathway also operates in the suppression of immune surveillance. In lung cancer cells, activation of GPR81 decreases intracellular cAMP levels and inhibits protein kinase A activity, leading to TAZ activation, which contributes to the activation of the programmed death ligand-1 PD-L1/PD-1 immune checkpoint and impairment of T cell function [54]. Moreover, GPR132, an additional sensor/receptor for lactate, that is specifically found in macrophages and is sensitive to repressive control by peroxisome proliferator-activated receptor (PPARγ), regulates breast tumour–macrophage interplay by promoting the M2-phenotype conversion, thereby promoting cancer metastasis [55].
    Strategies to Target Lactate Metabolism and Signalling Based on the aforementioned involvement of lactate in supporting tumour initiation and progression, impairing lactate homeostasis is a promising approach for cancer therapeutics. For the sake of completeness, any alterations in the expression and/or function of the players that contribute to the maintenance of deregulated glucose and/or glutamine metabolic pathways will inevitably impact on lactate production and release. For instance, PI3K activation, aberrant MYC expression, and HIF1-dependent signalling are all pro-glycolytic and/or pro-glutaminolytic events that have been shown to be potentially targetable, and positive results have been reported in preclinical and clinical cancer models 56, 57, 58. The success of these approaches may be due in part to disruption of lactate homeostasis. However, it is difficult to ascertain the actual contribution of altered lactate homeostasis given the multiple signalling and metabolic events that these molecular players control. In the following we highlight recent findings obtained by using available molecules that are known to target lactate production and transport, focusing in particular on LDH and MCTs (Figure 1).