This Title All WIREs
How to cite this WIREs title:
WIREs Syst Biol Med
Impact Factor: 2.385

Metabolism in cancer metastasis: bioenergetics, biosynthesis, and beyond

Full article on Wiley Online Library:   HTML PDF

Can't access this content? Tell your librarian.

Metabolic changes accompany tumor progression and metastatic dissemination of cancer cells. Yet, until recently, metabolism has received little attention in the study of cancer metastasis. Cancer cells undergo significant metabolic rewiring as they acquire metastatic traits and adapt to survive in multiple environments with varying nutrient availability, oxygen concentrations, and extracellular signals. Therefore, to effectively treat metastatic cancer, it is important to understand the metabolic strategies adopted by cancer cells during the metastatic process. Here, we focus on the metabolic pathways known to play a role in cancer metastasis, including glycolysis, the pentose phosphate pathway, tricarboxylic acid cycle, oxidative phosphorylation, amino acid metabolism, and fatty acid metabolism. Recent studies have uncovered roles for these pathways in cellular events that promote metastasis, including reactive oxygen species‐mediated signaling, epigenetic regulation, and interaction with the extracellular matrix. We also discuss the metabolic interplay between immune cells and cancer cells supporting metastasis. Finally, we highlight the current limitations of our knowledge on this topic, and present future directions for the field.

Metabolic and signaling pathways involving reactive oxygen species (ROS) in metastatic cells. ROS is generated during oxidative phosphorylation (OXPHOS), which is driven by tricarboxylic acid (TCA) cycle activity as well as proline degradation. Besides glycolysis, glutaminolysis, and fatty acid oxidation all contribute to the TCA cycle. ROS production is balanced by the glutathione cycle, which eliminates excess ROS. The glutathione cycle is driven by NADPH, produced from the pentose phosphate pathway, folate cycle as well as a noncanonical pathway involving pyruvate generation from mitochondrial aspartate‐derived oxaloacetate. Green text and arrows denote metabolites and metabolic reactions, respectively. Red and black arrows represent regulatory relationships (black, activation; red, inhibition). Blue text denote genes or gene products. Black text denote cellular processes or mechanisms. 5,10‐CH2‐THF, 5,10‐methylene‐tetrahydrofolate; EGFR, epidermal growth factor receptor; GLS, glutaminase; GSH, glutathione (reduced); GSSG, glutathione disulfide (oxidized); HIF1‐α, hypoxia‐inducible factor1‐α; ME1, malic enzyme 1 (cytosolic); MDH1, malate dehydrogenase; P5C, Δ1‐pyrroline‐5‐carboxylate; PHD2, prolyl hydroxylase domain‐containing protein 2; PKM2, pyruvate kinase isozyme M2; PYK2, protein tyrosine kinase 2; THF, tetrahydrofolate.
[ Normal View | Magnified View ]
Metabolic pathways affecting epigenetic regulation in metastatic cells. Reactions in one‐carbon metabolism affect the supply of S‐adenosylmethionine (SAM), which is the universal donor of methyl groups for DNA and histone methylation reactions. SAM is produced from methionine and is utilized in the conversion of glycine to sarcosine. Glycine may be regenerated from sarcosine via a folate cycle‐coupled reaction. Proline has also been shown to induce histone methylation. Meanwhile, tricarboxylic acid (TCA) cycle metabolites affect DNA and histone demethylation reactions. α‐ketoglutarate (αKG) is the co‐substrate for ten‐eleven translocation (TET) 5‐methylcytosine hydroxylases and histone demethylases, and is competitively inhibited by the oncometabolites 2‐hydroxyglutarate, succinate, and fumarate. Metastatic progression may result from either aberrant activation of oncogenes due to DNA/histone hypomethylation, or silencing of tumor suppressor genes due to DNA/histone hypermethylation. 5,10‐CH2‐THF, 5,10‐methylene‐tetrahydrofolate; FH, fumarate hydratase; GNMT, glycine N‐methyltransferase; 2HG, 2‐hydroxyglutarate; IDH, isocitrate dehydrogenase; PIPOX, pipecolic acid oxidase; SAH, S‐adenosyl homocysteine; SAM, S‐adenosylmethionine; SARDH, sarcosine dehydrogenase; SDH, succinate dehydrogenase; THF, tetrahydrofolate.
[ Normal View | Magnified View ]
Metabolites implicated in inhibition of cancer‐suppressive T‐cell function. (a) T cells require glucose as well as amino acids arginine, tryptophan, and cysteine for activation, proliferation, and function. Functional T cells inhibit tumor growth and metastatic spread. (b) Tumor cells or tumor‐associated macrophages (TAMs) may deplete these substrates from either the tumor microenvironment or the distal site to suppress normal T‐cell function and allow metastatic spread. Nitric oxide (NO) and kynurenines, produced from arginine and tryptophan, respectively, also directly inhibit T‐cell function as well as inducing T‐cell apoptosis. In addition, extracellular ROS released by TAMs catalyze the nitration of amino acid residues on T‐cell receptors and disrupt effector T‐cell function. ARG1, arginase; IDO, indoleamine 2,3‐dioxygenase; iNOS2, inducible nitric oxide synthase‐2; NOX, NADPH oxidase; ROS, reactive oxygen species.
[ Normal View | Magnified View ]
Overview of major metabolic pathways discussed in this review. Metabolic enzymes are highlighted in blue. The metabolic pathway map can be roughly divided into the following segments: (a) glycolysis; (b) pentose phosphate pathway; (c) TCA cycle and OXPHOS; (d) one‐carbon metabolism; and (e) fatty acid metabolism. 3PG, 3‐phosphoglycerate; 5,10‐CH2‐THF, 5,10‐methylene‐tetrahydrofolate; 5‐CH3‐THF, 5‐methyl‐tetrahydrofolate; 6PG, 6‐phosphogluconate; 6PGL, 6‐phosphogluconolactone; ACP, acyl carrier protein; CoA, coenzyme A; DHAP, dihydroxyacetone phosphate; E4P, erythrose 4‐phosphate; F6P, fructose 6‐phosphate; FASN, fatty acid synthase; FBP, fructose 1,6‐biphosphate; FH, fumarate hydratase; G6P, glucose 6‐phosphate; G6PDH, glucose‐6‐phosphate dehydrogenase; G6PDH, glucose‐6‐phosphate dehydrogenase; GAP, glyceraldehyde 3‐phosphate; GDH, glutamate dehydrogenases; GLS, glutaminase; GMNT, glycine N‐methyltransferase; GOT1, glutamic‐oxaloacetic transaminase 1 (cytoplasmic); GOT2, glutamic‐oxaloacetic transaminase 2 (mitochondrial); HK, hexose kinase; IDH, isocitrate dehydrogenase; MDH1, malate dehydrogenase 1 (cytosolic); ME1, malic enzyme 1 (cytosolic); P5CS, pyrroline‐5‐carboxylate synthase; PEP, phosphoenolpyruvate; PFKFB, 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase; PGLS, 6‐phosphogluconolactonase; PGLS, 6‐phosphogluconolactonase; PHGDH, 3‐phosphoglycerate dehydrogenase; PKM, pyruvate kinase; PKM, pyruvate kinase; PRODH, proline dehydrogenase; R5P, ribose 5‐phosphate; Ru5P, ribulose 5‐phosphate; S7P, seduheptulose 7‐phosphate; SAH, S‐adenosyl homocysteine; SAM, S‐adenosyl methionine; SDH, succinate dehydrogenase; SHMT, serine hydroxymethyltransferase; THF, tetrahydrofolate; TKT, transketolase.; X5P, xylulose 5‐phosphate; αKG, α‐ketoglutarate.
[ Normal View | Magnified View ]

Browse by Topic

Biological Mechanisms > Metabolism

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

The latest WIREs articles in your inbox

Sign Up for Article Alerts

In the Spotlight

Jens Nielsen

Jens Nielsen
is a Professor in the Department of Biology and Biological Engineering at Chalmers University of Technology in Göteborg, Sweden. His research focus is on systems biology of metabolism. The yeast Saccharomyces cerevisiae is the lab’s key organism for experimental research, but they also work with Aspergilli oryzae.

Learn More