The Emerging Hallmarks of Cancer Metabolism

Abstract

Tumorigenesis is dependent on the reprogramming of cellular metabolism as both direct and indirect consequence of oncogenic mutations. A common feature of cancer cell metabolism is the ability to acquire necessary nutrients from a frequently nutrient-poor environment and utilize these nutrients to both maintain viability and build new biomass. The alterations in intracellular and extracellular metabolites that can accompany cancer-associated metabolic reprogramming have profound effects on gene expression, cellular differentiation, and the tumor microenvironment. In this Perspective, we have organized known cancer-associated metabolic changes into six hallmarks: (1) deregulated uptake of glucose and amino acids, (2) use of opportunistic modes of nutrient acquisition, (3) use of glycolysis/TCA cycle intermediates for biosynthesis and NADPH production, (4) increased demand for nitrogen, (5) alterations in metabolite-driven gene regulation, and (6) metabolic interactions with the microenvironment. While few tumors display all six hallmarks, most display several. The specific hallmarks exhibited by an individual tumor may ultimately contribute to better tumor classification and aid in directing treatment.

Figure 1. The emerging hallmarks of cancer metabolism

Cancer cells accumulate metabolic alterations that allow them to gain access to conventional nutrient sources as well as to unconventional nutrient sources, utilize these nutrients towards the creation of new biomass to sustain deregulated proliferation, and take advantage of the ability of select metabolites to affect the fate of cancer cells themselves as well as a variety of normal cell types within the tumor microenvironment. Three layers of cell-metabolite interaction are depicted, all of which become reprogrammed in cancer. On top are the adaptations that involve nutrient uptake (Hallmarks 1 and 2), followed by alterations to intracellular metabolic pathways (Hallmarks 3 and 4) in the middle. Finally, long-ranging effects of metabolic reprogramming on the cancer cell itself (Hallmark 5), as well as on other cells within its microenvironment (Hallmark 6) are depicted at the bottom.

Figure 2. Deregulated uptake of glucose and amino acids

Aberrantly activated oncogenes and loss of tumor suppressors deregulates the import of glucose and amino acids into cancer cells. Solid arrows depict the movement of metabolites or proteins and metabolic reactions. Dashed arrows depict positive and negative regulatory effects of signal transduction components. RTK, receptor tyrosine kinase; GLUT1, glucose transporter 1; ASCT2/SN2, glutamine transporter; LAT1, neutral amino acid transporter; EAA, essential amino acids; GLS1, glutaminase 1; PRPS2, phosphoribosyl pyrophosphate synthetase 2; CAD, carbamoyl-phosphate synthetase 2; HK, hexokinase; ECM, extracellular matrix.

Figure 3. Use of opportunistic modes of nutrient acquisition

When free amino acids are unavailable, cancer cells may recover amino acids from (a) extracellular proteins via macropinocytosis. MPS, macropinosome, Lys, lysosome, (b) entosis of living cells, or (c) phagocytosis of apoptotic bodies. d, in conditions of oxygen deficiency, which prevents the de novo desaturation of stearate (C18:0) into oleate (C18:1), monounsaturated fatty acids such as oleate (C18:1) can be recovered from extracellular lysophospholipids (LPL). MPC, macropinocytosis; SCD1, stearoyl-CoA desaturase 1. X represents a lipid head group.

Figure 4. Use of glycolysis/TCA cycle intermediates for biosynthesis and NADH production

a, differences in the central carbon metabolism of a cell in a quiescent state compared to a proliferating cell; b, diverse biosynthetic outputs of central carbon metabolism. RTK, receptor tyrosine kinase; GLUT1, glucose transporter 1; PKM2, pyruvate kinase M2; ACSS2, acetyl-CoA synthetase 2; LDH-A, lactate dehydrogenase A; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase 1; ACLY, ATP-citrate lyase; MCT1, monocarboxylate transporter 1; ASCT2/SN2, glutamine transporter.

Figure 5. Increased demand for nitrogen

Sources of nitrogen atoms and regulation of nucleotide and polyamine biosynthesis. PRPP, phosphoribosyl pyrophosphate; PRPS2, phosphoribosyl pyrophosphate synthetase 2; CAD, carbamoyl-phosphate synthetase 2; Gln, glutamine, Glu, glutamate; Gly, glycine; Asp, aspartate; Fum, fumarate; IMPDH1/2, inosine-5-monophosphate dehydrogenase; TS, thymidylate synthase; GMPS, guanosine monophosphate synthetase; DCK, deoxycytidine kinase; TK, thymidine kinase, ARG1, arginase 1; ODC, ornithine decarboxylase; CAT1/2, cationic amino acid transporter.

Figure 6. Alterations in metabolite-driven gene regulation

Diverse metabolites serve as cofactors or substrates for enzymes involved in deposition and removal of epigenetic marks. HAT, histone acetyltransferase enzymes; Ac, an acetyl mark; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; DNMT, DNA methyltransferase enzymes; HMT, histone methyltransferase enzymes; Me, a methyl mark; LSD1, lysine-specific histone demethylase 1; JHDM, Jumonji domain-containing histone demethylase enzymes; Cyt, cytosine; ^5meCyt, 5-methylcytosine; ^5hmCyt, 5-hydroxymethylcytosine; TET1/2, ten-eleven translocation methylcytosine dioxygenase 1/2; α-KG, α-ketoglutarate; SDH, succinate dehydrogenase; FH, fumarate hydratase; IDH1/2, isocitrate dehydrogenase 1/2.

Figure 7. Metabolic interactions with the microenvironment

Cancer cells alter the chemical composition of the extracellular milieu, which exerts pleiotropic effects on the phenotypes of normal cells that reside in the vicinity of the tumor, as well as the extracellular matrix. Reciprocally, the microenvironment affects the metabolism and signaling responses of cancer cells themselves. ECM, extracellular matrix; Treg, regulatory T cells; HA, hyaluronic acid; MMPs, matrix metalloproteinases; MCT1, monocarboxylate transporter 1; CAIX, carbonic anhydrase IX; IDO1, indoleamine-2, 3-dioxygenase 1; TDO2, tryptophan-2, 3-dioxygenase 2; Kyn, kynurenine; AhR, aryl -hydrocarbon receptor.