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  • A similar symbiotic relationship has been

    2021-11-26

    A similar symbiotic relationship has been reported in the brain, where increased gradients of lactate secreted by astrocytes enables neurons to import and use this nutrient, a process referred to the ‘neuron–astrocyte lactate shuttle’ [16]. Similarly, lactate-based metabolic coupling established by cancer ha141 australia and stromal cells is another example of ‘two-compartment metabolic coupling’ [17]. Such a process is well-described in CAF coupled with prostate and breast carcinoma cells models. CAFs grown in contact with cancer cells activate glucose transporter (e.g., GLUT1) expression, enhancing glucose uptake and MCT4-mediated lactate release (Box 2). Concurrently, glycolytic activity is repressed in prostate cancer cells because they begin to metabolize CAF-derived lactate [18], undergoing metabolic dependence that is associated with growth, the acquisition of stem-like traits, and metastasis. Interestingly, reciprocal MCT1 and MCT4 expression in epithelial and stromal compartments correlates with activation of an antioxidant response in lactate-importing cells that are primed and adapted to oxidative stress by stromal lactate [19]. However, the other side of the coin is that CAFs represent cells that are able to exploit tumour cell-derived lactate. Indeed, Apicella et al. showed that patient-derived lung and gastric tumour cells that are resistant to c-Met inhibitors educate CAFs to upload and utilize lactate, triggering proinflammatory circuits upstream of aberrant stromal HGF production and driving drug resistance in tumours [20]. In parallel to data from our laboratory focusing on the ability of CAF-derived lactate to sculpt prostate cancer metabolism 18, 21, a recent study describing the metabolism of lactate in human lung tumours in vivo shows that exogenous lactate enters via MCT1 and is consumed and used in preference to glucose as a respiratory fuel for the TCA cycle [8]. Notably, the preferential enrichment in lactate, over other metabolic fuels, defines a key metabolic signature of lactate-derived pyruvate carboxylation in human non-small-cell lung carcinoma (NSCLC) beyond TCA cycle replenishment [2], thereby corroborating the key contribution of stroma in supplying lactate for mitochondrial exploitation [22]. Accordingly, it has been shown that tumour cells can maximize metabolic flexibility by adapting TCA cycle and mitochondria-related pathways, allowing the cancer cells to respond to environmental metabolic cues, thereby promoting proliferation and metastasis [23]. Notably, gradients of extracellular lactate in the TME orchestrate spatial and phenotypic patterns in additional stromal cells such as macrophages. Indeed, lactate accumulation in ischemic tumour regions correlates with infiltration and activation of tumour-associated macrophages (TAMs). Intriguingly, lactate-sensing in TAMs drives communication with endothelial cells for the revascularization of these regions, thus allowing tumour growth [24]. Consistently, the lactate-rich environment shaped by cancer cells is able to educate recruited macrophages into M2-polarized TAMs, and this confers a tumour growth advantage in vivo[25]. Finally, lactate has also been identified as a crucial component that contributes to the immunosuppressive TME (Figure 2). It was earlier reported that CD4+ and CD8+ T cell subsets, upon entering inflammatory sites, sense high concentrations of lactate via MCT2 and MCT1 transporters, respectively, and detrimentally undergo inactivation because of lactate-mediated motility inhibition [26]. Crucially, metabolic competition between cancer cells and immune cells (mostly T and natural killer, NK, cells) underlies tumour progression: indeed, Warburg metabolism competitively provides cancer cells with an advantage, resulting in depletion of extracellular glucose and in massive lactate release, at the expense of tumour-infiltrating T cells that become dysfunctional [27]. In keeping with this observation, pancreatic tumours highly expressing MCT4 negatively impact on the surrounding immune milieu[28]. In addition, the glycolytic imbalance found in melanomas expressing high LDHA level reflects a highly metastatic outcome because LDHAhigh tumour cells are stronger competitors for glucose and acidify the TME, thus dampening interferon-γ (IFN-γ) production by CD8+ T and NK cells and inhibiting their cytolytic activity [29]. Tumour-secreted lactate also inhibits NK function by stimulating the recruitment of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) [30]. Notably, NK cell activation via the NKG2D receptor is further suppressed by NKG2D ligand-bearing myeloid cells recruited to the TME in response to extracellular LDH (LDH5) [31].