Key Points
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During the past decade, the metabolic alterations that intimately accompany oncogenesis and tumour progression have been intensively investigated, generating great expectations on the development of novel antineoplastic agents that would selectively target the metabolism of malignant cells.
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With the notable exception of oncometabolites, the metabolism of cancer cells resembles very much that of any rapidly proliferating cell, exhibiting a prominent shift towards anabolic reactions and an increased dependency on intermediates and pathways that — directly or indirectly — sustain such an accelerated biosynthetic activity.
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At least in some settings, systemic metabolism exerts a prominent influence on carcinogenesis and tumour progression. This is best exemplified by the increased risk of developing cancer that accompanies metabolic syndromes such as diabetes and obesity as well as by the antineoplastic effects of several drugs that are currently used for the treatment of these conditions.
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The extensive metabolic rewiring of malignant cells is not yet another hallmark of cancer but instead a process that intervenes along with — and hence cannot be discriminated from — oncogenesis. In line with this notion, multiple oncogenes (for example, MYC) and oncosuppressor genes (for example, the tumour suppressor p53 gene TP53) have been shown to regulate bioenergetic and anabolic metabolic circuitries.
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The accumulation of metabolic intermediates such as fumarate, succinate and 2-hydroxyglutarate suffices to drive oncogenesis, at least in some settings. The existence of such oncometabolites reinforces the notion that the metabolic rearrangements of malignant cells are not a mere epiphenomenon of oncogenesis but one of its crucial components.
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A huge amount of preclinical data and accumulating clinical experience indicate that several metabolic circuitries can be efficiently targeted to achieve antineoplastic effects in vivo. Thus, in spite of an essential similarity between the metabolism of cancer cells and that of any highly proliferating cell, a therapeutic window exists for this promising approach to treat cancer.
Abstract
Malignant cells exhibit metabolic changes, when compared to their normal counterparts, owing to both genetic and epigenetic alterations. Although such a metabolic rewiring has recently been indicated as yet another general hallmark of cancer, accumulating evidence suggests that the metabolic alterations of each neoplasm represent a molecular signature that intimately accompanies and allows for different facets of malignant transformation. During the past decade, targeting cancer metabolism has emerged as a promising strategy for the development of selective antineoplastic agents. Here, we discuss the intimate relationship between metabolism and malignancy, focusing on strategies through which this central aspect of tumour biology might be turned into cancer's Achilles heel.
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Change history
29 November 2013
There were some inaccuracies in a sentence on p839 of the article. The correct sentence is as follows: "Along similar lines, the pharmacological or genetic inhibition of phosphoglycerate mutase 1 (PGAM1) reduces tumour growth in vitro and in vivo, perhaps owing (at least in part) to the PPP-inhibitory effects of 3-phosphoglycerate222. That said, genetic defects that have an impact on the enzymatic activity of G6PD (and hence inhibit the PPP) are common among individuals living in geographical areas with a history of endemic malaria223". This has now been corrected in the online version of the article.
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Acknowledgements
The authors are supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR); AXA Chair for Longevity Research; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Institut National du Cancer (INCa); Fondation Bettencourt-Schueller; Fondation de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI).
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Supplementary information S1 (table)
Metabolic targets for cancer therapy (PDF 416 kb)
Glossary
- 18F-deoxyglucose positron emission tomography
-
(18FDG–PET). An imaging procedure that is widely used in oncology for diagnostic, staging or monitoring purposes. 18FDG–PET relies on a radioactive glucose analogue that is preferentially taken up and retained by malignant cells in the context of the Warburg effect.
- Pentose phosphate pathway
-
(PPP). A metabolic circuitry (also known as phosphogluconate pathway or hexose monophosphate shunt) that converts glycolytic intermediates (mainly glucose-6-phosphate, fructose-6-phosphate and glyceraldehyde-3-phosphate) into pentoses (5-carbon sugars) and NADPH.
- Macroautophagy
-
An evolutionarily conserved mechanism that targets intracellular components for lysosomal degradation. Macroautophagy has a major role in the maintenance of intracellular homeostasis as well as in the response of cells to adverse microenvironmental conditions, including nutrient deprivation and hypoxia.
- Lactate shuttle
-
A cell-extrinsic metabolic circuitry that is based on the release of glycolytic lactate from one cell type (for example, astrocytes) and its uptake by another cell type (for example, neurons), which uses lactate to fuel oxidative phosphorylation.
- Lactic acidosis
-
A medical condition (also known as metabolic acidosis) that is characterized by a reduction in the pH of tissues and blood, and is often caused by the extracellular accumulation of lactate.
- Ketogenic diet
-
A high-fat, adequate-protein, low-carbohydrate diet that forces an organism to produce energy mostly via fatty acid oxidation rather than via the catabolism of carbohydrates. This is generally associated with an increase in the levels of circulating ketone bodies, which have beneficial effects in some forms of epilepsy.
- 2-hydroxyglutarate
-
(2-HG). An oncometabolite originating from the reduction of α-ketoglutarate as catalysed by the neomorphic enzymatic activity associated with specific isocitrate dehydrogenase mutations.
- Hexokinase 2
-
(HK2). A member of an enzyme family that catalyses the essentially irreversible phosphorylation of glucose to glucose-6-phosphate, de facto trapping it in the cytoplasm and rendering it available for metabolic processes including glycolysis or glycogen synthesis.
- Anaplerotic conversion
-
Reaction that contributes to the replenishment of metabolic intermediates involved in a metabolic circuitry but does not pertain to the same circuitry. A classic example of anaplerosis refers to the replenishment of Krebs cycle intermediates via the direct conversion of pyruvate (or aspartate) into oxaloacetate, glutamate into α-ketoglutarate, or adenylosuccinate into fumarate.
- Lactate dehydrogenase A
-
(LDHA). A member of the LDH family. LDH is an abundant cytosolic enzyme that catalyses the reversible conversion of pyruvate and NADH into lactate and NAD+.
- Mitochondrial apoptosis
-
A regulated signal transduction cascade leading to the apoptotic demise of cells upon the permeabilization of mitochondrial membranes, resulting in the functional impairment of mitochondria and in the release of cytotoxic proteins into the cytosol.
- Succinate dehydrogenase
-
(SDH). An enzyme of the inner mitochondrial membrane that catalyses the oxidation of succinate to fumarate, which is coupled to the reduction of ubiquinone to ubiquinol, de facto being simultaneously involved in the Krebs cycle and in mitochondrial respiration.
- Fumarate hydratase
-
(FH). An enzyme that catalyses the reversible hydration of fumarate to malate. The mitochondrial isoenzyme of FH is involved in the Krebs cycle.
- Isocitrate dehydrogenase
-
(IDH). An enzyme that catalyses the reversible oxidative decarboxylation of isocitrate, producing α-ketoglutarate and carbon dioxide. The mitochondrial isoenzyme (IDH2) is involved in the Krebs cycle.
- Oncometabolite
-
A small chemical produced in the context of intermediate metabolism that is sufficient to promote oncogenesis following its accumulation.
- Carbonic anhydrase
-
One of several zinc-containing enzymes that catalyses the reversible conversion of carbon dioxide and water into carbonic acid (H2CO3), which — in physiological conditions — rapidly dissociates into H+ and HCO3−, thus exerting a major pH-regulatory function.
- Glutamate dehydrogenase 1
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(GLUD1). A mitochondrial enzyme that catalyses the essentially irreversible conversion of α-ketoglutarate into glutamate and ammonia. The reverse (anaplerotic) reaction is highly unfavoured in mammals owing to the very low affinity of GLUD1 for ammonia.
- Carnitine shuttle
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A multi-enzymatic system that relies on carnitine as a recyclable vehicle for the import of cytosolic fatty acids into the mitochondrial matrix.
- Apcmin/+ mice
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Mice harbouring a heterozygous mutation that results in the expression of a truncated form of adenomatosis polyposis coli (APC). Owing to this alteration, Apcmin/+ mice can develop up to 100 polyps in the small intestine as well as colorectal tumours.
- Auxotrophic
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The state of cells or organisms that are unable to synthesize a metabolite that is strictly required for their own survival or growth.
- Rapalogue
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Any of several chemical agents that resemble rapamycin in its capacity to inhibit the enzymatic activity of mammalian target of rapamycin.
- Antimetabolites
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Any of several antineoplastic drugs that operate, at least in part, by inhibiting the metabolism of nucleic acids. Several antimetabolites are currently approved for use in patients with cancer.
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Galluzzi, L., Kepp, O., Heiden, M. et al. Metabolic targets for cancer therapy. Nat Rev Drug Discov 12, 829–846 (2013). https://doi.org/10.1038/nrd4145
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DOI: https://doi.org/10.1038/nrd4145
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