Influence of a pro-inflammatory stimulus on the miRNA and lipid content of human dental stem cell-derived extracellular vesicles and their impact on microglial activation.

Neuro-inflammation occurs in numerous disorders such as multiple sclerosis, Alzheimer's disease and Parkinson's disease. However, anti-inflammatory drugs for the central nervous system have failed to show significant improvement when compared to a placebo in clinical trials. Our previous work demonstrated that stem cells from the apical papilla (SCAP) can decrease neuro-inflammation and stimulate oligodendrocyte progenitor cell differentiation. One hypothesis is that the therapeutic effect of SCAP could be mediated by their secretome, including extracellular vesicles (EV). Here, our objectives were to characterize SCAP-EV and to study their effect on microglial cells. We isolated EV from non-activated SCAP and from SCAP activated with TNFα and IFN-γ and characterized them according to their size, EV markers, miRNA and lipid content. Their ability to decrease pro-inflammatory cytokine expression in vitro and ex vivo was also assessed. We showed that the miRNA content was impacted by a pro-inflammatory environment but not their lipid composition. SCAP-EV reduced the expression of pro-inflammatory markers in LPS-activated microglial cells while their effect was limited on mouse spinal cord sections. In conclusion, we were able to isolate EV from SCAP, to show that their miRNA content was impacted by a pro-inflammatory stimulus, and to describe that SCAP-EV and not the protein fraction of conditioned medium could reduce pro-inflammatory marker expression in LPS-activated BV2 cells.

MitoQ Prevents Human Breast Cancer Recurrence and Lung Metastasis in Mice.

In oncology, the occurrence of distant metastases often marks the transition from curative to palliative care. Such outcome is highly predictable for breast cancer patients, even if tumors are detected early, and there is no specific treatment to prevent metastasis. Previous observations indicated that cancer cell mitochondria are bioenergetic sensors of the tumor microenvironment that produce superoxide to promote evasion. Here, we tested whether mitochondria-targeted antioxidant MitoQ is capable to prevent metastasis in the MDA-MB-231 model of triple-negative human breast cancer in mice and in the MMTV-PyMT model of spontaneously metastatic mouse breast cancer. At clinically relevant doses, we report that MitoQ not only prevented metastatic take and dissemination, but also local recurrence after surgery. We further provide in vitro evidence that MitoQ does not interfere with conventional chemotherapies used to treat breast cancer patients. Since MitoQ already successfully passed Phase I safety clinical trials, our preclinical data collectively provide a strong incentive to test this drug for the prevention of cancer dissemination and relapse in clinical trials with breast cancer patients.

MitoQ Inhibits Human Breast Cancer Cell Migration, Invasion and Clonogenicity.

To successfully generate distant metastases, metastatic progenitor cells must simultaneously possess mesenchymal characteristics, resist to anoïkis, migrate and invade directionally, resist to redox and shear stresses in the systemic circulation, and possess stem cell characteristics. These cells primarily originate from metabolically hostile areas of the primary tumor, where oxygen and nutrient deprivation, together with metabolic waste accumulation, exert a strong selection pressure promoting evasion. Here, we followed the hypothesis according to which metastasis as a whole implies the existence of metabolic sensors. Among others, mitochondria are singled out as a major source of superoxide that supports the metastatic phenotype. Molecularly, stressed cancer cells increase mitochondrial superoxide production, which activates the transforming growth factor-ß pathway through src directly within mitochondria, ultimately activating focal adhesion kinase Pyk2. The existence of mitochondria-targeted antioxidants constitutes an opportunity to interfere with the metastatic process. Here, using aggressive triple-negative and HER2-positive human breast cancer cell lines as models, we report that MitoQ inhibits all the metastatic traits that we tested in vitro. Compared to other mitochondria-targeted antioxidants, MitoQ already successfully passed Phase I safety clinical trials, which provides an important incentive for future preclinical and clinical evaluations of this drug for the prevention of breast cancer metastasis.

Single-cell RNA sequencing of human liver reveals hepatic stellate cell heterogeneity.

BACKGROUND & AIMS: The multiple vital functions of the human liver are performed by highly specialised parenchymal and non-parenchymal cells organised in complex collaborative sinusoidal units. Although crucial for homeostasis, the cellular make-up of the human liver remains to be fully elucidated. Here, single-cell RNA-sequencing was used to unravel the heterogeneity of human liver cells, in particular of hepatocytes (HEPs) and hepatic stellate cells (HSCs). METHOD: The transcriptome of ~25,000 freshly isolated human liver cells was profiled using droplet-based RNA-sequencing. Recently published data sets and RNA in situ hybridisation were integrated to validate and locate newly identified cell populations. RESULTS: In total, 22 cell populations were annotated that reflected the heterogeneity of human parenchymal and non-parenchymal liver cells. More than 20,000 HEPs were ordered along the portocentral axis to confirm known, and reveal previously undescribed, zonated liver functions. The existence of 2 subpopulations of human HSCs with unique gene expression signatures and distinct intralobular localisation was revealed (i.e. portal and central vein-concentrated GPC3 + HSCs and perisinusoidally located DBH + HSCs). In particular, these data suggest that, although both subpopulations collaborate in the production and organisation of extracellular matrix, GPC3 + HSCs specifically express genes involved in the metabolism of glycosaminoglycans, whereas DBH + HSCs display a gene signature that is reminiscent of antigen-presenting cells. CONCLUSIONS: This study highlights metabolic zonation as a key determinant of HEP transcriptomic heterogeneity and, for the first time, outlines the existence of heterogeneous HSC subpopulations in the human liver. These findings call for further research on the functional implications of liver cell heterogeneity in health and disease. LAY SUMMARY: This study resolves the cellular landscape of the human liver in an unbiased manner and at high resolution to provide new insights into human liver cell biology. The results highlight the physiological heterogeneity of human hepatic stellate cells.

Human Liver-Derived Extracellular Matrix for the Culture of Distinct Human Primary Liver Cells.

The lack of robust methods to preserve, purify and in vitro maintain the phenotype of the human liver's highly specialized parenchymal and non-parenchymal cell types importantly hampers their exploitation for the development of research and clinical applications. There is in this regard a growing interest in the use of tissue-specific extracellular matrix (ECM) to provide cells with an in vitro environment that more closely resembles that of the native tissue. In the present study, we have developed a method that allows for the isolation and downstream application of the human liver's main cell types from cryopreserved material. We also isolated and solubilized human liver ECM (HL-ECM), analyzed its peptidomic and proteomic composition by mass spectrometry and evaluated its interest for the culture of distinct primary human liver cells. Our analysis of the HL-ECM revealed proteomic diversity, type 1 collagen abundance and partial loss of integrity following solubilization. Solubilized HL-ECM was evaluated either as a coating or as a medium supplement for the culture of human primary hepatocytes, hepatic stellate cells and liver sinusoidal endothelial cells. Whereas the solubilized HL-ECM was suitable for cell culture, its impact on the phenotype and/or functionality of the human liver cells was limited. Our study provides a first detailed characterization of solubilized HL-ECM and a first report of its influence on the culture of distinct human primary liver cells.

Monocarboxylate transporters in cancer.

BACKGROUND: Tumors are highly plastic metabolic entities composed of cancer and host cells that can adopt different metabolic phenotypes. For energy production, cancer cells may use 4 main fuels that are shuttled in 5 different metabolic pathways. Glucose fuels glycolysis that can be coupled to the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in oxidative cancer cells or to lactic fermentation in proliferating and in hypoxic cancer cells. Lipids fuel lipolysis, glutamine fuels glutaminolysis, and lactate fuels the oxidative pathway of lactate, all of which are coupled to the TCA cycle and OXPHOS for energy production. This review focuses on the latter metabolic pathway. SCOPE OF REVIEW: Lactate, which is prominently produced by glycolytic cells in tumors, was only recently recognized as a major fuel for oxidative cancer cells and as a signaling agent. Its exchanges across membranes are gated by monocarboxylate transporters MCT1-4. This review summarizes the current knowledge about MCT structure, regulation and functions in cancer, with a specific focus on lactate metabolism, lactate-induced angiogenesis and MCT-dependent cancer metastasis. It also describes lactate signaling via cell surface lactate receptor GPR81. MAJOR CONCLUSIONS: Lactate and MCTs, especially MCT1 and MCT4, are important contributors to tumor aggressiveness. Analyses of MCT-deficient (MCT+/- and MCT-/-) animals and (MCT-mutated) humans indicate that they are druggable, with MCT1 inhibitors being in advanced development phase and MCT4 inhibitors still in the discovery phase. Imaging lactate fluxes non-invasively using a lactate tracer for positron emission tomography would further help to identify responders to the treatments.

Presenilin-Deficient Neurons and Astrocytes Display Normal Mitochondrial Phenotypes.

Presenilin 1 (PS1) and Presenilin 2 (PS2) are predominantly known as the catalytic subunits of the γ-secretase complex that generates the amyloid-ß (Aß) peptide, the major constituent of the senile plaques found in the brain of Alzheimer's disease (AD) patients. Apart from their role in γ-secretase activity, a growing number of cellular functions have been recently attributed to PSs. Notably, PSs were found to be enriched in mitochondria-associated membranes (MAMs) where mitochondria and endoplasmic reticulum (ER) interact. PS2 was more specifically reported to regulate calcium shuttling between these two organelles by controlling the formation of functional MAMs. We have previously demonstrated in mouse embryonic fibroblasts (MEF) an altered mitochondrial morphology along with reduced mitochondrial respiration and increased glycolysis in PS2-deficient cells (PS2KO). This phenotype was restored by the stable re-expression of human PS2. Still, all these results were obtained in immortalized cells, and one bottom-line question is to know whether these observations hold true in central nervous system (CNS) cells. To that end, we carried out primary cultures of PS1 knockdown (KD), PS2KO, and PS1KD/PS2KO (PSdKO) neurons and astrocytes. They were obtained from the same litter by crossing PS2 heterozygous; PS1 floxed (PS2+/-; PS1flox/flox) animals. Genetic downregulation of PS1 was achieved by lentiviral expression of the Cre recombinase in primary cultures. Strikingly, we did not observe any mitochondrial phenotype in PS1KD, PS2KO, or PSdKO primary cultures in basal conditions. Mitochondrial respiration and membrane potential were similar in all models, as were the glycolytic flux and NAD+/NADH ratio. Likewise, mitochondrial morphology and content was unaltered by PS expression. We further investigated the differences between results we obtained here in primary nerve cells and those previously reported in MEF cell lines by analyzing PS2KO primary fibroblasts. We found no mitochondrial dysfunction in this model, in line with observations in PS2KO primary neurons and astrocytes. Together, our results indicate that the mitochondrial phenotype observed in immortalized PS2-deficient cell lines cannot be extrapolated to primary neurons, astrocytes, and even to primary fibroblasts. The PS-dependent mitochondrial phenotype reported so far might therefore be the consequence of a cell immortalization process and should be critically reconsidered regarding its relevance to AD.

Prolonged inhibition and incomplete recovery of mitochondrial function in oxazolidinone-treated megakaryoblastic cell lines.

Thrombocytopenia is commonly seen in patients receiving linezolid for >14 days. Linezolid is a reversible inhibitor of mitochondrial function in various cell types. This study investigated the inhibitory effects of linezolid and tedizolid, and their potential recovery on (i) CYTox I expression (subunit I of cytochrome c-oxidase; encoded by the mitochondrial genome), (ii) cytochrome c-oxidase activity and (iii) mitochondrial respiration (Seahorse bioanalysis) in two megakaryocytic cell lines [UT-7 WT (human acute megakaryoblastic leukaemia cells) and UT-7 MPL (transduced to express the thrombopoietin receptor)]. Cells were exposed to linezolid (0.5-25 mg/L) or tedizolid (0.1-5 mg/L) for up to 5 days and recovery followed after drug removal. Both oxazolidinones caused concentration- and time-dependent inhibition of CYTox I expression, cytochrome c-oxidase activity and mitochondrial spare capacity. On electron microscopy, mitochondria appeared dilated with a loss of cristae. Globally, tedizolid exerted stronger effects than linezolid. While CYTox I expression recovered completely after 6 days of drug washout, only partial (linezolid) or no (tedizolid) recovery of cytochrome c-oxidase activity, and no rescue of mitochondrial spare capacity (after 3 days) was observed. Thus, and in contrast to previous studies using a variety of cell lines unrelated to megakaryocytic lineages, the inhibitory effects exerted by oxazolidinones on the mitochondrial function of megakaryoblastic cells appear to be particularly protracted. Given the dynamics of platelet production and destruction, these results may explain why oxazolidinone-induced thrombocytopenia is one of the most common side effects in patients exposed to these antibiotics.

Pro- and antitumor effects of mitochondrial reactive oxygen species.

In cancer, mitochondrial functions are commonly altered. Directly involved in metabolic reprogramming, mitochondrial plasticity confers to cancer cells a high degree of adaptability to a wide range of stresses and to the harsh tumor microenvironment. Lack of nutrients or oxygen caused by altered perfusion, metabolic needs of proliferating cells, co-option of the microenvironment, control of the immune system, cell migration and metastasis, and evasion of exogenous stress (e.g., chemotherapy) are all, at least in part, influenced by mitochondria. Mitochondria are undoubtedly one of the key contributors to cancer development and progression. Understanding their protumoral (dys)functions may pave the way to therapeutic strategies capable of turning them into innocent entities. Here, we will focus on the production and detoxification of mitochondrial reactive oxygen species (mtROS), on their impact on tumorigenesis (genetic, prosurvival, and microenvironmental effects and their involvement in autophagy), and on tumor metastasis. We will also summarize the latest therapeutic approaches involving mtROS.

PLGA: From a classic drug carrier to a novel therapeutic activity contributor.

Poly(lactic-co-glycolic acid) (PLGA) is well known for its biocompatibility and minimal toxicity. It is one of the most promising biodegradable polymeric drug delivery systems able to get endorsement from regulatory bodies to enter market. For many decades, PLGA has been functioning as an excipient, which by definition is pharmaceutically inert at a given dose of formulation. Lactate (one of the hydrolysis products of PLGA) has a key role in biochemical pathways and could improve physiological activities in certain illnesses by exerting therapeutic effects such as angiogenesis and promotion of healing. These activities, however, depend on the released amounts and metabolic clearance of lactate and route of formulation delivery. In the current commentary, along with several key notes on the lactate interactions, we would like to inform the PLGA research community that lactate (resulting from local delivery of physiologically significant amount of PLGA) may positively or negatively affect therapeutic efficacy of certain drugs. Hence, the excipient role of PLGA may be investigated for its potential pharmacological contributions in some biomedical applications.

Mitochondrial Alterations (Inhibition of Mitochondrial Protein Expression, Oxidative Metabolism, and Ultrastructure) Induced by Linezolid and Tedizolid at Clinically Relevant Concentrations in Cultured Human HL-60 Promyelocytes and THP-1 Monocytes.

Linezolid, the first clinically available oxazolidinone antibiotic, causes potentially severe toxicities (myelosuppression, lactic acidosis, and neuropathies) ascribed to impairment of mitochondrial protein synthesis and consecutive mitochondrial dysfunction. Tedizolid, a newly approved oxazolidinone, shows an enhanced activity compared to linezolid but is also a more potent inhibitor of mitochondrial protein synthesis. We compared linezolid and tedizolid for (i) inhibition of the expression of subunit I of cytochrome c-oxidase (CYTox I; Western blot analysis), (ii) cytochrome c-oxidase activity (biochemical assay), (iii) mitochondrial oxidative metabolism (Seahorse technology), and (iv) alteration of mitochondrial ultrastructure (electron microscopy) using HL-60 promyelocytes and THP-1 monocytes exposed to microbiologically (multiples of modal MIC against Staphylococcus aureus) and therapeutically (Cmin - Cmax) pertinent concentrations. Both drugs caused a rapid and complete (48 to 72 h) inhibition of CYTox I expression, cytochrome c-oxidase activity, and spare respiratory capacity, with conspicuous swelling of the mitochondrial matrix and loss of their cristae. Globally, tedizolid was a more potent inhibitor than linezolid. For both drugs, all effects were quickly (48 to 72 h) and fully reversible upon drug withdrawal. Using an alternation of exposure to and withdrawal from drug mimicking their approved schedule of administration (twice daily and once daily [qD] for linezolid and tedizolid, respectively), only partial inhibition of CYTox I expression was noted for up to 96 h. Thus, rapid reversal of toxic effects upon discontinuous administration may mitigate oxazolidinone toxicity. Since tedizolid is given qD, this may help to explain its reported lower preclinical and clinical toxicity.

(+)-Catechin in a 1:2 Complex with Lysine Inhibits Cancer Cell Migration and Metastatic Take in Mice.

Metastasis is of dismal prognosis for cancer patients, but recent evidence in mouse models of cancer shows that metastasis prevention is a reachable clinical objective. These experiments indicate that altered mitochondrial activities are associated with the metastatic phenotype. Mitochondrial transfer from metastatic to non-metastatic cells can indeed transfer the metastatic phenotype, and metastatic progenitor cells differ from other cancer cells by a higher sublethal production of mitochondrial reactive oxygen species (ROS). Moreover, mitochondria-targeted antioxidants can prevent metastatic dissemination in mouse models of cancer. Comparatively, general antioxidants have unpredictable effects on cancer metastasis, most probably because they affect several cell types, several subcellular ROS production sites and, often, several endogenous oxidant species. Thus, targeting antioxidants to mitochondria could improve their antimetastatic activities, as previously exemplified with mitochondria-targeted mitoTEMPO and mitoQ that can prevent metastatic dissemination in cancer-bearing mice. Our objective in this study was to identify whether catechins, which are known to be potent antioxidants, can inhibit cancer cell migration in vitro and metastatic take in vivo. Comparative analysis of the response to epigallocatechin-3-gallate, (+)-catechin and (+)-catechin:lysine complexes revealed that, whereas all compounds had similar general antioxidant properties, (+)-catechin:lysine 1:2, but not epigallocatechin-3-gallate, can prevent metastatic take of melanoma cells to the lungs of mice. (+)-Catechin:lysine 1:2 possesses two net positive charges provided by lysines at physiological pH, which could provide high affinity for the negatively charged mitochondrial matrix. While this study reveals that (+)-catechin:lysine 1:2 has interesting antimetastatic effects, future experiments are needed to formally demonstrate the stability of the complex, its effective tropism for mitochondria and whether or not its activity can be globally attributed to its antioxidant activity at this precise subcellular location.

Monocarboxylate Transporter MCT1 Promotes Tumor Metastasis Independently of Its Activity as a Lactate Transporter.

Extracellular acidosis resulting from intense metabolic activities in tumors promotes cancer cell migration, invasion, and metastasis. Although host cells die at low extracellular pH, cancer cells resist, as they are well equipped with transporters and enzymes to regulate intracellular pH homeostasis. A low extracellular pH further activates proteolytic enzymes that remodel the extracellular matrix to facilitate cell migration and invasion. Monocarboxylate transporter MCT1 is a passive transporter of lactic acid that has attracted interest as a target for small-molecule drugs to prevent metastasis. In this study, we present evidence of a function for MCT1 in metastasis beyond its role as a transporter of lactic acid. MCT1 activates transcription factor NF-κB to promote cancer cell migration independently of MCT1 transporter activity. Although pharmacologic MCT1 inhibition did not modulate MCT1-dependent cancer cell migration, silencing or genetic deletion of MCT1 in vivo inhibited migration, invasion, and spontaneous metastasis. Our findings raise the possibility that pharmacologic inhibitors of MCT1-mediated lactic acid transport may not effectively prevent metastatic dissemination of cancer cells. Cancer Res; 77(20); 5591-601. ©2017 AACR.

Cancer metabolism in space and time: Beyond the Warburg effect.

Altered metabolism in cancer cells is pivotal for tumor growth, most notably by providing energy, reducing equivalents and building blocks while several metabolites exert a signaling function promoting tumor growth and progression. A cancer tissue cannot be simply reduced to a bulk of proliferating cells. Tumors are indeed complex and dynamic structures where single cells can heterogeneously perform various biological activities with different metabolic requirements. Because tumors are composed of different types of cells with metabolic activities affected by different spatial and temporal contexts, it is important to address metabolism taking into account cellular and biological heterogeneity. In this review, we describe this heterogeneity also in metabolic fluxes, thus showing the relative contribution of different metabolic activities to tumor progression according to the cellular context. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.

Monocarboxylate transporters in the brain and in cancer.

Monocarboxylate transporters (MCTs) constitute a family of 14 members among which MCT1-4 facilitate the passive transport of monocarboxylates such as lactate, pyruvate and ketone bodies together with protons across cell membranes. Their anchorage and activity at the plasma membrane requires interaction with chaperon protein such as basigin/CD147 and embigin/gp70. MCT1-4 are expressed in different tissues where they play important roles in physiological and pathological processes. This review focuses on the brain and on cancer. In the brain, MCTs control the delivery of lactate, produced by astrocytes, to neurons, where it is used as an oxidative fuel. Consequently, MCT dysfunctions are associated with pathologies of the central nervous system encompassing neurodegeneration and cognitive defects, epilepsy and metabolic disorders. In tumors, MCTs control the exchange of lactate and other monocarboxylates between glycolytic and oxidative cancer cells, between stromal and cancer cells and between glycolytic cells and endothelial cells. Lactate is not only a metabolic waste for glycolytic cells and a metabolic fuel for oxidative cells, but it also behaves as a signaling agent that promotes angiogenesis and as an immunosuppressive metabolite. Because MCTs gate the activities of lactate, drugs targeting these transporters have been developed that could constitute new anticancer treatments. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.

Direct Evidence of the Link Between Energetic Metabolism and Proliferation Capacity of Cancer Cells In Vitro.

The aim of the study was to assess the link between the metabolic profile and the proliferation capacity of a range of human and murine cancer cell lines. First, the combination of mitochondrial respiration and glycolytic efficiency measurements allowed the determination of different metabolic profiles among the cell lines, ranging from a mostly oxidative to a mostly glycolytic phenotype. Second, the study revealed that cell proliferation, evaluated by DNA synthesis measurements, was statistically correlated to glycolytic efficiency. This indicated that glycolysis is the key energetic pathway linked to cell proliferation rate. Third, to validate this hypothesis and exclude non-metabolic factors, mitochondria-depleted were compared to wild-type cancer cells, and the data showed that enhanced glycolysis observed in mitochondria-depleted cells is also associated with an increase in proliferation capacity.

Inhibition of the pentose phosphate pathway by dichloroacetate unravels a missing link between aerobic glycolysis and cancer cell proliferation.

Glucose fermentation through glycolysis even in the presence of oxygen (Warburg effect) is a common feature of cancer cells increasingly considered as an enticing target in clinical development. This study aimed to analyze the link between metabolism, energy stores and proliferation rates in cancer cells. We found that cell proliferation, evaluated by DNA synthesis quantification, is correlated to glycolytic efficiency in six cancer cell lines as well as in isogenic cancer cell lines. To further investigate the link between glycolysis and proliferation, a pharmacological inhibitor of the pentose phosphate pathway (PPP) was used. We demonstrated that reduction of PPP activity decreases cancer cells proliferation, with a profound effect in Warburg-phenotype cancer cells. The crucial role of the PPP in sustaining cancer cells proliferation was confirmed using siRNAs against glucose-6-phosphate dehydrogenase, the first and rate-limiting enzyme of the PPP. In addition, we found that dichloroacetate (DCA), a new clinically tested compound, induced a switch of glycolytic cancer cells to a more oxidative phenotype and decreased proliferation. By demonstrating that DCA decreased the activity of the PPP, we provide a new mechanism by which DCA controls cancer cells proliferation.

Metabolic changes associated with tumor metastasis, part 2: Mitochondria, lipid and amino acid metabolism.

Metabolic alterations are a hallmark of cancer controlling tumor progression and metastasis. Among the various metabolic phenotypes encountered in tumors, this review focuses on the contributions of mitochondria, lipid and amino acid metabolism to the metastatic process. Tumor cells require functional mitochondria to grow, proliferate and metastasize, but shifts in mitochondrial activities confer pro-metastatic traits encompassing increased production of mitochondrial reactive oxygen species (mtROS), enhanced resistance to apoptosis and the increased or de novo production of metabolic intermediates of the TCA cycle behaving as oncometabolites, including succinate, fumarate, and D-2-hydroxyglutarate that control energy production, biosynthesis and the redox state. Lipid metabolism and the metabolism of amino acids, such as glutamine, glutamate and proline are also currently emerging as focal control points of cancer metastasis.

Metabolic changes associated with tumor metastasis, part 1: tumor pH, glycolysis and the pentose phosphate pathway.

Metabolic adaptations are intimately associated with changes in cell behavior. Cancers are characterized by a high metabolic plasticity resulting from mutations and the selection of metabolic phenotypes conferring growth and invasive advantages. While metabolic plasticity allows cancer cells to cope with various microenvironmental situations that can be encountered in a primary tumor, there is increasing evidence that metabolism is also a major driver of cancer metastasis. Rather than a general switch promoting metastasis as a whole, a succession of metabolic adaptations is more likely needed to promote different steps of the metastatic process. This review addresses the contribution of pH, glycolysis and the pentose phosphate pathway, and a companion paper summarizes current knowledge regarding the contribution of mitochondria, lipids and amino acid metabolism. Extracellular acidification, intracellular alkalinization, the glycolytic enzyme phosphoglucose isomerase acting as an autocrine cytokine, lactate and the pentose phosphate pathway are emerging as important factors controlling cancer metastasis.

Common responses of tumors and wounds to hypoxia.

Hypoxia is a characteristic of tumors and wounds. Hypoxic cells develop 2 common strategies to face hypoxia: the glycolytic switch and the angiogenic switch. At the onset of hypoxia, alleviation of the Pasteur effect ensures short-term cell survival. Long-term hypoxic cell survival requires a further acceleration of the glycolytic flux under the control of hypoxia-inducible factor 1 that stimulates the expression of most glycolytic transporters and enzymes, uncouples glycolysis from the TCA cycle, and rewires glycolysis to lactic fermentation. Hypoxic cells also trigger angiogenesis, a process that aims to restore normal microenvironmental conditions. Transcription factors (hypoxia-inducible factor 1, nuclear factor κB, activator protein 1) and lactate cooperate to stimulate the expression of proangiogenic agents. Cancer cells differ from normal hypoxic cells by their proliferative agenda and by a high metabolic heterogeneity. These effects in tumor account for further molecular and metabolic changes and for a persistent stimulation of angiogenesis.