The stress of accelerated lactate production

The stress of accelerated lactate production in cancer Mupirocin is moderated by the overexpression of lactate transporters – symporters for lactate anions and protons called monocarboxylate transporters (MCTs) – that are capable of bidirectional transport depending on the environmental and/or cellular context (Box 1). Lactate released via MCTs by lactate biosynthesis-addicted cells is an energy-rich byproduct that is exploited by several cells within the TME (see below), mainly by uploading it via MCT1 [5]. Secretion of lactate is typical of several cancer histotypes, as well as of all cancer cells exposed to hypoxia (or pseudohypoxia). In addition, stromal cells may be a relevant source of lactate (Box 2). Therefore, it is conceivable that, within a given tumour mass, a subset of cells undergoes Warburg-like metabolism whereas another subset further catabolise the lactate via OXPHOS-dependent metabolism. However, lactate levels are remarkably elevated in glycolytic tumours (1–40mM) [6] and correlate with cancer aggressiveness and poor survival 7, 8. The net increase in lactate levels within the tumour is possibly due (i) to the higher glucose-to-lactate flux (that characterise Warburg-dependent cells) versus the lactate-to-CO2 flux of lactate-dependent cells and (ii) to the high number of Warburg-dependent cells that is characteristic of a fast-growing tumour, a feature that is measured with fluorodeoxyglucose (FDG)–positron emission tomography (PET) in clinical practice to monitor tumour growth and dissemination. In addition to being used as a metabolite, lactate within the TME serves multiple purposes, including signalling among cell populations, epigenetic reprogramming, and nutritional aims [9]. Glycolytic cancer cells and cancer-associated fibroblasts (CAFs) are the main source of lactate, simply because they are the most abundant populations within the neoplasm, and also contribute lactate for nutritional purposes. By contrast, M1 macrophages and glycolytic T cells are rare populations in tumours and contribute lactate molecules useful for signalling and epigenetic reconditioning of cells uploading lactate. Warburg metabolism of cancer (or cancer-accessory) cells has been correlated with the generation of building blocks needed to fuel cell proliferation [1]. The strong increase of glucose uptake, as a result of glycolytic inefficiency and increased requirement for ATP causes the accumulation of several intermediates that fuel anabolic pathways converging on protein and DNA synthesis, thereby allowing cell growth. Of note, lactate biosynthesis does not include all carbon skeletons incorporated into glucose-addicted cells undergoing Warburg metabolism because a substantial fraction of these carbons accumulates in glycolytic intermediates and fuels anabolic pathways stemming from glycolysis. Expression of the M2 isozyme of pyruvate kinase (PKM2), an enzyme acting as a bottleneck at the end of cancer cell glycolysis owing to its frequent inhibition, further enhances the accumulation of glycolytic intermediates, thereby fuelling diverse metabolic pathways exploiting glucose and contributing not only to lactate biosynthesis but also to the synthesis of biomolecules [10]. In this scenario, lactate biosynthesis is a collateral pathway that is apparently only necessary to rescue NAD+ levels to allow maintenance of glycolysis. In addition, lactate biosynthesis should be acknowledged to exert an additional role: it produces a molecule that is strongly active within TME, both as a nutrient and as a signalling molecule with hormone-like properties. Because it acts as: (i) an energy-rich substrate, (ii) a molecule able to affect epigenetics, and (iii) a soluble hormone ‘sensed’ by a membrane receptor, lactate has been referred to as a ‘lactormone’ [11].
Lactate Rewires the Tumour Microenvironment and Powers Tumour Malignancy Reasonably, lactate is placed in this scenario as an exchangeable molecule between cells, and not exclusively for its established role as a mere glycolytic byproduct (Figure 1). It has been reported that oxygenated cancer cells, close to blood vessels, are sustained by a favourable location with high nutritional availability, and can establish a metabolic symbiosis with hypoxic cancer cells, a phenomenon that is essential for the progression of a fast-growing tumour characterized by hypoxic regions. Indeed, because glucose is mainly diverted to fuel the glycolytic metabolism of distant hypoxic cancer cells, oxygenated cancer cells adopt an oxidative metabolism based on lactate discarded from hypoxic cancer cells through MCT4, whose expression is directly controlled by hypoxia, and that is uploaded by oxygenated tumour cells via MCT1 [5]. Oxidative cancer cells primed by lactate are more prone to glutaminolysis by increasing the expression of glutamine transporter ASCT2 and glutaminase 1 (GLS1) to fuel the TCA cycle [12]. Conversely, in glycolytic cancer, glutaminolysis is only a secondary source for lactate production [12]. In addition, extensive investigations have shown that lactate metabolic coupling exploits the reversible reaction of lactate dehydrogenase (LDH). In a scenario of tissue heterogeneity, it is likely that cells uploading lactate use LDH isoform B to convert lactate into pyruvate, while cells producing lactate preferentially use LDHA to fuel canonical lactate biosynthesis (Box 3). Indeed, upon MCT1-mediated entry, lactate and NAD+ are converted into pyruvate, NADH, and H+ by LDHB. Then, while pyruvate and NADH fuel oxidative mitochondrial metabolism, protons generated by LDHB are able to promote V-ATPase-dependent lysosomal acidification and autophagy, constituting an additional source of energetic and biosynthetic precursors in metabolically restricted microenvironments [13]. Importantly, metabolic symbiosis between MCT4-expressing hypoxic cells and MCT1-expressing oxygenated cells stimulates resistance to antiangiogenic therapy in murine and human models, in which mTOR pathway inhibition represents a selective way to destroy the perivascular MCT1-positive subpopulation that is resistant to antiangiogenic inhibitors [14]. Conversely, resistance to PI3K/mTOR inhibitors occurs in breast cancer cells actively engaging lactate oxidation, a metabolic adaptive pathway adopted to withstand fluctuations in glucose availability [15].