The emerging hallmarks of cancer metabolism

Tumorigenesis depends on reprogramming cellular metabolism as a direct and indirect consequence of oncogenic mutations.

“Tumorigenesis is dependent on the reprogramming of cellular metabolism as both direct and indirect consequence of oncogenic mutations.”

Intracellular glutamine may facilitate import of a broad range of LAT1 substrates including leucine, isoleucine, valine, methionine, tyrosine, tryptophan, and phenylalanine.

“In such a manner, intracellular glutamine may facilitate the import of a broad range of LAT1 substrates, including leucine, isoleucine, valine, methionine, tyrosine, tryptophan and phenylalanine”

• cites Yanagida et al., 2001 sourceNot checked yet

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Growth factor-deprived hematopoietic and neuronal cells fail to consume glucose in quantities sufficient to maintain cellular bioenergetics.

“when deprived of growth factors, hematopoietic and neuronal cells fail to consume glucose in quantities sufficient to even maintain cellular bioenergetics”

• cites Lindsten et al., 2003 sourceNot checked yet

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• cites Rathmell et al., 2000 sourceNot checked yet

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Optimal growth of cultured HeLa cells requires a 10- to 100-fold molar excess of glutamine relative to other amino acids.

“the optimal growth of cultured HeLa cells requires a 10- to a 100-fold molar excess of glutamine in culture medium relative to other amino acids”

• cites Eagle, 1955 sourceNot checked yet

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Glutamine provides nitrogen for biosynthesis of purine and pyrimidine nucleotides, glucosamine-6-phosphate, and non-essential amino acids.

“Thus, glutamine provides the nitrogen required for the biosynthesis of purine and pyrimidine nucleotides, glucosamine-6-phosphate, as well as non-essential amino acids.”

Glutamine is the most rapidly consumed amino acid by Ehrlich ascites carcinomas and several hepatomas and carcinosarcomas proliferating in vivo.

“glutamine was found to be the most rapidly consumed amino acid by Ehrlich ascites carcinomas as well as by a number of hepatomas and carcinosarcomas proliferating in vivo”

• cites Marquez et al., 1989 sourceNot checked yet

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• cites Sauer et al., 1982Not checked yet

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Glutamine contributes carbon and reduced nitrogen for de novo biosynthesis of nitrogen-containing compounds.

“Glutamine, a second principal growth-supporting substrate contributes not only carbon, but also reduced nitrogen for the de novo biosynthesis of a number of diverse nitrogen-containing compounds.”

Numerous tumorigenic contexts are associated with depletion of glutamine from the tumor environment compared to normal tissue.

“numerous tumorigenic contexts are associated with the depletion of glutamine from the tumor environment as compared to the corresponding normal tissue”

• cites Marquez et al., 1989 sourceNot checked yet

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• cites Rivera et al., 1988 sourceNot checked yet

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• cites Roberts and Frankel, 1949Not checked yet

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Alterations in intracellular and extracellular metabolites accompanying cancer metabolic reprogramming have profound effects on gene expression, cellular differentiation, and the tumor microenvironment.

“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.”

Catabolism of glucose and glutamine maintains pools of carbon intermediates used as building blocks for macromolecules.

“Through the catabolism of glucose and glutamine, a cell maintains pools of diverse carbon intermediates, which are utilized as building blocks for the assembly of various macromolecules.”

Import of leucine through LAT1 is coupled to simultaneous efflux of glutamine.

“the import of an essential amino acid leucine through the plasma membrane-localized neutral amino acid antiporter LAT1 was shown to be coupled to a simultaneous efflux of glutamine”

• cites Nicklin et al., 2009 sourceNot checked yet

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Markedly increased glucose consumption by tumors compared to non-proliferating normal tissues was first described by Warburg.

“A markedly increased consumption of glucose by tumors in comparison to the non-proliferating normal tissues was first described more than 90 years ago by the German physiologist Otto Warburg”

• cites Warburg O, 1924Not checked yet

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• cites Warburg et al., 1927 sourceNot checked yet

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Survival of growth-factor deprived cells can be restored by combined expression of GLUT1 and hexokinase.

“survival of growth-factor deprived cells can be readily restored by a combined expression of a plasma membrane glucose transporter GLUT1 and the first enzyme of the glycolytic pathway hexokinase (HK)”

• cites Rathmell et al., 2003 sourceNot checked yet

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A common feature of cancer cell metabolism is the ability to acquire necessary nutrients from a nutrient-poor environment and use them to maintain viability and build biomass.

“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.”

Reprogramming of carbon metabolism by proliferating cells provides part of the explanation for Warburg's original observations.

“The reprogramming of carbon metabolism by proliferating cells provides part of the explanation for Warburg’s original observations concerning cancer metabolism.”

Targeted depletion of mitochondrial DNA reduces the tumorigenic potential of cancer cell lines in vitro and in vivo.

“targeted depletion of mitochondrial DNA reduces the tumorigenic potential of cancer cell lines in vitro and in vivo”

• cites Cavalli et al., 1997Not checked yet

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• cites Morais et al., 1994Not checked yet

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• cites Tan et al., 2015 sourceNot checked yet

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The major use of reduced carbon in proliferating cells is biosynthesis of biomolecules including fatty acids, cholesterol, pentose and hexose sugar derivatives, glycerol, nucleotides, and non-essential amino acids.

“The major use of reduced carbon in proliferating cells is for the biosynthesis of a diverse array of biomolecules – among which are fatty acids and cholesterol, pentose and hexose sugar derivatives, glycerol, nucleotides and non-essential amino acids.”

Aberrantly activated oncogenes and/or loss of tumor suppressors can lock cancer cells in a state of constitutive scavenging of glucose, glutamine, and essential amino acids, enabling uncontrolled proliferation.

“aberrantly activated oncogenes and/or loss of tumor suppressors can lock cancer cells in a state where they constitutively scavenge available glucose, glutamine and essential amino acids from the extracellular environment, which, in turn, enables their uncontrolled proliferation.”

Expression of mutant Ras or c-Src provides a mechanism to recover free amino acids through lysosomal degradation of extracellular proteins.

“expression of mutant Ras or c-Src alleles provides cells with a mechanism that allows them to recover free amino acids through the lysosomal degradation of extracellular proteins”

• cites Commisso et al., 2013 sourceNot checked yet

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Lack of vascular nutrient delivery in growing tumors causes hypoxic areas, suppressing biosynthetic reactions requiring molecular oxygen.

“A second consequence of a lack of vascular nutrient delivery in growing tumors is an emergence of hypoxic areas, which leads to a suppression of a number of biosynthetic reactions that require molecular oxygen as an electron acceptor.”

Cancer cells accumulate oncogenic alterations that convey significant independence from external requirements for survival and proliferation.

“cancer cells accumulate oncogenic alterations that convey to them a significant degree of independence from these external requirements”

• cites Hanahan and Weinberg, 2000 sourceNot checked yet

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• cites Vogelstein and Kinzler, 2004Not checked yet

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Proliferating cells have only a modest increase in ATP consumption relative to their need for precursor molecules and NADPH.

“proliferating cells have only a modest increase in their consumption of ATP relative to their need for precursor molecules and reducing equivalents in the form of NADPH.”

Glucose influx into cells is not driven by immediate bioenergetic needs but is rationed by extracellular stimuli.

“Taken together, these observations suggest that the influx of glucose into cells is not driven by the immediate bioenergetic needs of a cell, but on the contrary, is rationed strictly as a result of extracellular stimuli.”

Warburg demonstrated with tumor slices ex vivo that despite massive glucose consumption and ambient oxygen, cancer cells did not use the bioenergetic benefits of coupling glycolysis to the TCA cycle and converted surplus pyruvate to lactate.

“Warburg demonstrated that despite consuming massive amounts of glucose and being exposed to ambient oxygen, cancer cells did not take advantage of the bioenergetic benefits offered by the coupling of glycolysis to the TCA cycle. On the contrary, when grown in glucose-rich medium, any cells converted the surplus pyruvate to lactate, which, in turn, was secreted into the extracellular environment.”

TCA cycle activity generating NADH and ATP is a major negative regulator of glucose metabolism.

“TCA cycle activity which generates NADH and ATP is the major negative regulator of glucose metabolism.”

Albumin supplementation restores proliferation of a KRASG12D-driven mouse pancreatic cancer line in medium devoid of all free amino acids.

“Albumin supplementation has even been shown to restore the proliferation of a KRASG12D-driven mouse pancreatic cancer line in the culture medium that was devoid of all free amino acids”

• cites Kamphorst et al., 2015 sourceNot checked yet

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Upregulation of FABP4 on metastatic ovarian cancer cells allows acquisition of fatty acids from omental adipocytes.

“upregulation of a long chain fatty acid-binding protein FABP4 on the surface of metastatic ovarian cancer cells allows them to acquire fatty acids directly from the adipocytes of the omental fat”

• cites Nieman et al., 2011 sourceNot checked yet

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Deletion of Atg7 changes lung tumors driven by KrasG12D and BrafV600E from malignant adenocarcinomas to benign oncocytomas.

“deletion of a core component of the autophagy machinery, Atg7, was shown to dramatically change the nature of lung tumors driven by KrasG12D and BrafV600E oncogenes from malignant adenocarcinomas to benign oncocytomas”

• cites Guo et al., 2013 sourceNot checked yet

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• cites Strohecker et al., 2013 sourceNot checked yet

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Preferential conversion of glucose into lactate has been demonstrated in genetically normal proliferating cells and virus-infected cells.

“preferential conversion of glucose into lactate has been later demonstrated in genetically normal proliferating cells, as well as in cells infected by viruses”

• cites Brand et al., 1986 sourceNot checked yet

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• cites Chambers et al., 2010 sourceNot checked yet

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• cites Noch and Khalili, 2012Not checked yet

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Multiple growth signaling nodes aberrantly activated in cancer share the ability to facilitate cellular access to glucose.

“Taken together, multiple growth signaling nodes that become aberrantly activated in cancer share an ability to facilitate cellular access to glucose, a principal metabolic substrate.”

The carbon economy of a proliferating cell differs dramatically from that of a quiescent cell.

“The carbon economy of a proliferating cell differs dramatically from that of a cell that is quiescent”

• cites Vander Heiden et al., 2009 sourceNot checked yet

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Cancer cells in vivo often encounter nutrient scarcity due to increased nutrient consumption and inadequate tumor vascular supply.

“cancer cells in vivo often encounter conditions of nutrient scarcity as a result of the increased rates of nutrient consumption and the inadequacies of the tumor vascular supply”

• cites Vaupel et al., 1989Not checked yet

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Deletion of Rb family proteins upregulates glutamine uptake and utilization via E2F-dependent upregulation of ASCT2 and GLS1.

“The deletion of Rb family proteins has been shown to upregulate the uptake and utilization of glutamine via the E2F-dependent upregulation of ASCT2 and GLS1”

• cites Reynolds et al., 2014 sourceNot checked yet

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Elevated expression of LPL and MAGL across diverse cancer subtypes correlates with invasiveness.

“An elevated expression of lipoprotein lipase (LPL) and monoacylglycerol lipase (MAGL) across diverse cancer subtypes and correlates with invasiveness”

• cites Kuemmerle et al., 2011 sourceNot checked yet

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• cites Nomura et al., 2010 sourceNot checked yet

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Supplementation with physiological levels (20-30 mg/mL) of serum albumin enables proliferation of KRASG12D-transformed MEFs in the absence of leucine.

“supplementation of culture medium with physiological levels (20–30 mg/mL) of serum albumin enables proliferation of KRASG12D-transformed MEFs in the absence of an essential amino acid leucine”

• cites Palm et al., 2015 sourceNot checked yet

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Tumor cells utilize opportunistic modes of nutrient acquisition to survive and proliferate in metabolically unfavorable conditions.

“Taken together, tumor cells utilize opportunistic modes of nutrient acquisition, which allow them to survive and proliferate in metabolically unfavorable conditions.”

Genetic alterations targeting PI3K, PTEN, INPP4B, and activating RTK mutations or amplifications result in constitutive glucose uptake and metabolism in diverse cancers.

“genetic alterations that target PI-3 kinase, its negative regulators PTEN and INPP4B, as well as activating mutations and gene amplifications in a variety of upstream receptor tyrosine kinases, result in constitutive glucose uptake and metabolism in diverse cancer types.”

c-myc is a principal driver of glutamine utilization by proliferating cells.

“The transcription factor c-myc, which is upregulated in proliferating cells and is frequently targeted by amplification in various tumor types, is a principal driver of glutamine utilization by proliferating cells”

• cites Wang et al., 2011bNot checked yet

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• cites Wise et al., 2008 sourceNot checked yet

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Autophagy cannot supply new biomass and thus cannot support proliferation in nutrient-poor conditions.

“However, autophagy cannot supply cells with new biomass and thus cannot support proliferation in nutrient-poor conditions.”

PI3K/Akt signaling acts as a master regulator of glucose uptake.

“PI3K/Akt signaling acts as a master regulator of glucose uptake.”

Glutamine uptake is negatively regulated by the Rb tumor suppressor family.

“glutamine uptake is also subject to negative regulation by the Rb tumor suppressor family of proteins.”

Cancer cells can withstand long periods of nutrient deprivation via macroautophagy.

“cancer cells can withstand long periods of nutrient deprivation via the self-catabolic process of macroautophagy”

• cites Boya et al., 2013 sourceNot checked yet

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Capture of extracellular macromolecules occurs through macropinocytosis, in which bulk extracellular fluid is taken up into giant vesicles.

“capture of extracellular macromolecules occurs through macropinocytosis, a process in which bulk extracellular fluid is taken up into giant vesicles”

• cites Kerr and Teasdale, 2009Not checked yet

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Hypoxia compromises SCD1-catalyzed introduction of double bonds into de novo fatty acids, creating a deficit of unsaturated fatty acids.

“hypoxia compromises stearoyl-CoA desaturase 1 (SCD1)-catalyzed introduction of double bonds into the de novo produced fatty acids, creating a deficit of unsaturated fatty acid species.”

Cells with mutant KRAS are more likely to perpetrate entosis than to be consumed.

“cells that harbor a mutant KRAS allele are more likely to perpetrate entosis than to be consumed in this process”

• cites Sun et al., 2014 sourceNot checked yet

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Autophagy allows nutrient- or growth factor-deprived cells to maintain viability in culture for weeks.

“autophagy allows nutrient- or growth factor-deprived cells to maintain their viability in culture for weeks”

• cites Lum et al., 2005 sourceNot checked yet

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Hypoxic cells import ready-made unsaturated fatty acids from the environment as lysophospholipids.

“hypoxic cells import “ready-made” unsaturated fatty acids from the surrounding environment in a form of single acyl chain-containing lysophospholipids”

• cites Kamphorst et al., 2013 sourceNot checked yet

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Serine's γ-carbon is transferred to THF by SHMT2 in mitochondria and SHMT1 in cytosol, generating 5,10-methylene-THF and glycine.

“its γ-carbon can be transferred to a carrier molecule, tetrahydrofolate (THF), in a reaction catalyzed by serine hydroxylmethyltransferase 2 (SHMT2) in the mitochondria, and SHMT1 in the cytosol, generating 5, 10-methylene-THF and glycine.”

Dichotomy in carbon utilization for biosynthetic versus bioenergetic purposes may explain why tumors retain oxidative phosphorylation capacity despite Warburg hypothesis.

“Such apparent dichotomy in utilization of carbon for either predominantly biosynthetic or predominantly bioenergetic purposes may explain why tumors retain the capacity for oxidative phosphorylation, despite the original hypothesis put forth by Otto Warburg.”

Proliferating cells often accumulate electron transport flux exceeding ATP synthase capacity, resulting in excess ROS.

“Even with these adaptations, proliferating cells often accumulate electron transport flux that exceeds the capacity of the ATP synthase, resulting in the formation of excess reactive oxygen species (ROS).”

OIS triggered by mutant BRAF or RAS alleles is associated with profound oxidative damage and irreversible growth arrest.

“Triggered by the introduction of a mutant BRAF or RAS alleles, OIS is associated with a profound oxidative damage and irreversible growth arrest (Courtois-Cox et al., 2008).”

• cites Courtois-Cox et al., 2008 sourceNot checked yet

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3-phosphoglycerate is used as a precursor for biosynthesis of serine, glycine, methyl donor groups, and NADPH.

“the use of 3-phosphoglycerate as a precursor for the biosynthesis of serine, glycine, and as a means to generate methyl donor groups and NADPH.”

Serine is a major substrate for the one-carbon/folate cycle.

“Serine has a unique metabolic role in the cell as a major substrate for the so-called one-carbon, or folate cycle.”

Emerging evidence favors the hypothesis that glycolysis is used by proliferating cells as a versatile production line generating metabolic intermediates for numerous biosynthetic processes.

“The emerging evidence favors the hypothesis that glycolysis is utilized by proliferating cells as a versatile production line that generates metabolic intermediates for numerous biosynthetic processes.”

Pentose phosphate pathway utilization is frequently elevated in tumorigenesis.

“Utilization of PPP is frequently elevated in tumorigenesis.”

PKM2 activity is highly regulated, unlike PKM1.

“Unlike PKM1, PKM2’s activity is highly regulated.”

• cites Chaneton et al., 2012; Christofk et al., 2008b; Ye et al., 2012Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Akt activates ACLY, which cleaves TCA-derived citrate into acetyl-CoA and oxaloacetate.

“To this end, Akt activates the ATP-citrate lyase (ACLY) enzyme, which catalyzes cytosol-localized cleavage of the TCA cycle-derived citrate into acetyl-CoA and oxaloacetate (Bauer et al., 2005; Berwick et al., 2002).”

• cites Bauer et al., 2005 sourceNot checked yet

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• cites Berwick et al., 2002 sourceNot checked yet

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Stepwise oxidation of one-carbon-THF species produces up to 50% of all cellular NADPH.

“stepwise oxidation of one-carbon-THF species was recently shown to produce up to 50% of all cellular NADPH”

• cites Fan et al., 2014 sourceNot checked yet

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c-myc coordinately increases expression of PDK1, LDH-A, and MCT1.

“For instance, c-myc coordinately increases the expression of PDK1, lactate dehydrogenase A (LDH-A), an enzyme which catalyzes the reductive conversion of pyruvate to lactate, and monocarboxylate transporter (MCT1), which facilitates the efflux of lactate into the extracellular space (Wahlstrom and Arsenian Henriksson, 2015).”

• cites Wahlstrom and Arsenian Henriksson, 2015Not checked yet

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To balance biosynthetic outputs of glycolysis with pyruvate for TCA cycle activity, proliferating cells evolved a mechanism regulating the last step of glycolysis.

“To balance biosynthetic outputs of glycolysis with its role in providing pyruvate that supports TCA cycle activity, proliferating cells have evolved a novel mechanism by which to regulate the last step of glycolysis.”

Alterations in the one-carbon pathway may be universally selected for in tumorigenesis.

“suggesting that alterations in the one-carbon pathway may be universally selected for in tumorigenesis”

Damaging consequences of ROS overproduction from overloaded ETC may underlie oncogene-induced cellular senescence (OIS).

“In fact, the damaging consequences of the overproduction of ROS from the overloaded electron transport chain may underlie the phenomenon of oncogene-induced cellular senescence (OIS).”

Fructose-6-phosphate can leave glycolysis and become a substrate for hexosamine biosynthesis.

“Fructose-6-phosphate, which follows glucose-6-phosphate in the glycolytic pathway, can also leave glycolysis and become utilized as a substrate for hexosamine biosynthesis.”

Growth factor-dependent signaling inhibits PKM2, causing glycolytic intermediates to accumulate until the cell's need for free serine is saturated.

“In such a manner, growth factor-dependent signal transduction inhibits PKM2, leading to accumulation of glycolytic intermediates until the growing cell’s need for a catabolizable pool of free serine is saturated.”

HIF1α stabilization by hypoxia or oncogenic contexts triggers coordinated transcriptional upregulation of LDH-A and PDK1.

“Finally, stabilization of HIF1α by hypoxia or in various oncogenic contexts also triggers coordinated transcriptional upregulation of LDH-A and PDK1 (Kim et al., 2006; Papandreou et al., 2006).”

• cites Kim et al., 2006 sourceNot checked yet

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• cites Papandreou et al., 2006 sourceNot checked yet

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Attenuation of PDH activity via ectopic PDK1 expression or RNAi depletion of PDP2 bypasses mutant BRAFV600E-induced OIS and potentiates tumorigenesis.

“Interestingly, attenuation of the activity of pyruvate dehydrogenase (PDH), a gatekeeper enzyme that converts pyruvate into acetyl-CoA, via the ectopic expression of its negative regulator pyruvate dehydrogenase kinase 1 (PDK1) or an RNAi-mediated depletion of a PDH phosphatase PDP2 was found to bypass mutant BRAFV600E-induced OIS and potentiate tumorigenesis (Kaplon et al., 2013).”

• cites Kaplon et al., 2013 sourceNot checked yet

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Oxaloacetate is converted to malate and re-imported into mitochondria to maintain anaplerosis.

“Oxaloacetate is converted to malate and re-imported into mitochondria to maintain anaplerosis”

TCF/β-catenin signaling upregulates MCT1 and PDK1 transcription.

“In addition to c-myc, TCF/β-catenin signaling has also been shown to upregulate MCT1 and PDK1 transcription (Pate et al., 2014).”

• cites Pate et al., 2014 sourceNot checked yet

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PKM2 can be allosterically activated by excess accumulation of other glucose metabolism byproducts including SAICAR, an intermediate of ribose-5-phosphate biosynthesis.

“In addition to serine, PKM2 can also be allosterically activated by excess accumulation of other byproducts of glucose metabolism including succinylaminoimidazolecarboxamide (SAICAR), an intermediate product of ribose-5-phosphate biosynthesis (Keller et al., 2012).”

• cites Keller et al., 2012 sourceNot checked yet

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Increased GPDH activity has been detected in prostate cancer cells, insulinomas, and carcinoid tumors.

“In fact, increased activity of GPDH has been detected in prostate cancer cells, insulinomas and carcinoid tumors (Chowdhury et al., 2005; MacDonald et al., 1990).”

• cites Chowdhury et al., 2005 sourceNot checked yet

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• cites MacDonald et al., 1990Not checked yet

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MTHFD2 is among the top three most frequently overexpressed metabolic enzymes in cancer.

“methylene tetrahydrofolate dehydrogenase 2 (MTHFD2), a component of the mitochondrial arm of the one-carbon pathway, was found to be among the top three most frequently overexpressed metabolic enzymes in cancer”

• cites Nilsson et al., 2014 sourceNot checked yet

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A variety of oncogenes contribute to the metabolic adaptations of proliferating cells outlined above.

“A variety of oncogenes have been shown to contribute to the metabolic adaptations of proliferating cells outlined above.”

Growth factor signaling promotes use of select TCA cycle intermediates for generating biosynthetic precursors.

“In addition to glycolytic intermediates, growth factor signaling promotes the use of select TCA cycle intermediates in the generation of biosynthetic precursors as well.”

One-carbon-THF species are used for biosynthesis of purines, thymidine, and S-adenosylmethionine.

“One-carbon-THF species are utilized as substrates for the biosynthesis of purines, thymidine, as well as in the production of S-adenosylmethionine, a principal substrate for cellular methylation reactions.”

Hypoxia-driven induction of SHMT2 protects cells from hypoxia-associated oxidative stress.

“hypoxia-driven induction of SHMT2 expression was shown to protect cells from hypoxia-associated oxidative stress”

• cites Ye et al., 2014Not checked yet

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Excess NADH from glycolysis is not imported into mitochondria solely through chemical shuttles but also used to convert DHAP into glycerol-3-phosphate that donates electrons directly into ETC via mGPDH on outer mitochondrial membrane.

“Excess NADH generated by glycolysis is not imported into mitochondria of proliferating cells solely through chemical shuttles but is also utilized to convert the glycolytic intermediate DHAP into glycerol-3-phosphate that donates electrons directly into the electron transport chain utilizing glycerol-3-phosphate dehydrogenase (mGPDH) localized to the outer mitochondrial membrane.”

Cancer cells may utilize as much as 50% of glucose-derived carbon in serine biosynthesis and subsequent catabolism.

“cancer cells may utilize as much as 50% of glucose-derived carbon in serine biosynthesis and its subsequent catabolism”

• cites Locasale et al., 2011 sourceNot checked yet

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Moderate ROS generated during respiration or by NADPH oxidases constitute signaling input contributing to maintenance of tumorigenic state.

“Whereas overproduction of ROS is detrimental to cell growth and survival, moderate levels of ROS, which are generated either during respiration or in a targeted manner by a class of NADPH oxidases, constitute an important signaling input that contributes to the maintenance of the tumorigenic state (Sullivan and Chandel, 2014).”

• cites Sullivan and Chandel, 2014Not checked yet

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Mitochondria are protected from excess glycolysis because pyruvate entering TCA cycle is channeled into citrate secreted into cytosol via mitochondrial tricarboxylate carrier and broken into acetyl-CoA and oxaloacetate.

“Mitochondria are protected further from excess glycolysis because any pyruvate that does enter the TCA cycle is channeled into citrate that is secreted into the cytosol through the mitochondrial tricarboxylate carrier and broken down into acetyl-CoA and oxaloacetate.”

PI3K/Akt activation allows a cell to expand its cytosolic acetyl-CoA pool, a substrate for de novo fatty acid biosynthesis.

“In particular, PI3K/Akt activation allows a cell to expand its cytosolic pool of acetyl-CoA, a substrate for the de novo biosynthesis of fatty acids.”

• cites Bauer et al., 2005 sourceNot checked yet

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• cites Berwick et al., 2002 sourceNot checked yet

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Electrons entering mitochondrial ETC through glycerol phosphate dehydrogenase and Complex I from mitochondrial conversion of malate to oxaloacetate are sufficient to maintain mitochondrial integrity and ATP production despite reduced catabolic TCA cycle activity.

“The electrons entering the mitochondrial electron transport chain through glycerol phosphate dehydrogenase activity and Complex I as a result of mitochondrial conversion of malate to oxaloacetate are sufficient to maintain both mitochondrial integrity and ATP production despite reduced catabolic TCA cycle activity.”

Biosynthesis of asparagine from aspartate, catalyzed by ASNS, utilizes amide nitrogen of glutamine.

“In contrast, biosynthesis of asparagine from aspartate, catalyzed by asparagine synthetase (ASNS), utilizes the amide nitrogen of glutamine.”

Glutamine synthetase is overexpressed in some cancers.

“Glutamine synthetase (GS) has been found to be overexpressed in some cancers (Osada et al., 2000);”

• cites Osada et al., 2000 sourceNot checked yet

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Assembly of pyrimidine and purine rings utilizes aspartate derived from transamination of oxaloacetate and glutamic acid, both catabolites of glutamine.

“In addition, the assembly of both pyrimidine and purine rings utilizes aspartate, which is derived from the transamination of the TCA cycle metabolite oxaloacetate and glutamic acid, both of which are catabolites of glutamine.”

Mutant p53 alleles facilitate expression of nucleotide biosynthesis genes including IMPDH1/2, GMPS, DCK, and TK1.

“Besides the regulatory inputs from c-myc, mutant p53 alleles have also been shown to facilitate expression of nucleotide biosynthesis genes, among which are IMPDH1 and 2, GMP synthetase (GMPS) and nucleoside salvage enzymes deoxycytidine kinase (DCK) and thymidine kinase (TK1) (Kollareddy et al., 2015).”

• cites Kollareddy et al., 2015 sourceNot checked yet

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To maintain ability to synthesize non-essential amino acids, their production must be balanced with anaplerotic influx into TCA cycle.

“To maintain the ability to synthesize these amino acids, their production must be carefully balanced with an anaplerotic influx into the cycle.”

Asparagine plays a crucial regulatory role in conditions of glutamine deprivation.

“Yet despite this, asparagine plays a crucial regulatory role in conditions of glutamine deprivation (Zhang et al., 2014).”

• cites Zhang et al., 2014 sourceNot checked yet

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Proliferating cells must synthesize nitrogen-containing molecules de novo, including nucleotides, non-essential amino acids, and polyamines.

“Indeed, a proliferating cell must synthesize a number of nitrogen-containing molecules de novo, including nucleotides, non-essential amino acids and polyamines.”

c-myc-regulated targets include PRPS2 and CAD.

“Among the c-myc-regulated targets are phosphoribosyl pyrophosphate synthetase 2 (PRPS2), which catalyzes a first step of purine biosynthesis, as well as carbamoyl phosphate synthetase II (CAD), which initiates the pyrimidine ring-building cascade (Cunningham et al., 2014; Eberhardy and Farnham, 2001; Mannava et al., 2008).”

• cites Cunningham et al., 2014 sourceNot checked yet

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• cites Eberhardy and Farnham, 2001Not checked yet

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• cites Mannava et al., 2008 sourceNot checked yet

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Anaplerotic entry of glucose-derived carbons into TCA cycle occurs via carboxylation of pyruvate to oxaloacetate catalyzed by PC.

“Anaplerotic entry of glucose-derived carbons into the TCA cycle takes place via carboxylation of pyruvate into the TCA cycle intermediate oxaloacetate, catalyzed by pyruvate carboxylase (PC).”

c-myc orchestrates nucleotide biosynthesis by upregulating expression of nucleotide biosynthesis enzymes.

“The oncogene c-myc orchestrates nucleotide biosynthesis by upregulating the expression of a number of nucleotide biosynthesis enzymes.”

Similar accumulation of glucose-derived glutamine within tumor tissue was observed in a mouse model of c-Met-driven liver cancer.

“furthermore, a similar accumulation of glucose-derived glutamine within the tumor tissue was observed in a mouse model of c-Met-driven liver cancer (Yuneva et al., 2012).”

• cites Yuneva et al., 2012 sourceNot checked yet

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Arginine becomes conditionally essential in some tumorigenic contexts.

“Arginine, despite being a non-essential amino acid, also becomes conditionally essential in some tumorigenic contexts (Figure 5).”

Oxidation of glutamine-derived α-ketoglutarate into oxaloacetate helps maintain ability of cells to synthesize citrate.

“Oxidation of glutamine-derived α-ketoglutarate into oxaloacetate not only helps to maintain the ability of cells to synthesize citrate.”

Acute lymphoblastic leukemia cells lack ASNS expression, leading to asparagine auxotrophy.

“In contrast, acute lymphoblastic leukemia cells lack ASNS expression, leading to asparagine auxotrophy.”

Transcriptional effects of c-myc and E2F result in enhanced cellular uptake of glutamine.

“As discussed above, the transcriptional effects of c-myc and E2F result in enhanced cellular uptake of glutamine.”

Asparagine is the only amino acid that mammalian cells do not catabolize.

“Though structurally similar to glutamine, asparagine is the only amino acid that mammalian cells do not catabolize.”

Tracing glucose-derived carbons in human patients and mouse models of glioblastoma and NSCLC reveals that in these contexts the principal source for TCA cycle intermediates is glucose, not glutamine.

“In fact, tracing the fate of glucose-derived carbons in human patients and in mouse models of glioblastoma and non-small cell lung carcinoma (NSCLC) reveals that at least in these tumorigenic contexts, the principal source for the TCA cycle intermediates is not glutamine, but glucose (Maher et al., 2012; Marin-Valencia et al., 2012; Sellers et al., 2015).”

• cites Maher et al., 2012 sourceNot checked yet

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• cites Marin-Valencia et al., 2012 sourceNot checked yet

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• cites Sellers et al., 2015 sourceNot checked yet

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Major anaplerotic substrate in growing cells is glutamine.

“The major anaplerotic substrate in growing cells is glutamine.”

Glutamine deprivation leads to S-phase cell cycle arrest in certain cellular contexts.

“Accordingly, glutamine levels have been shown to be rate-limiting for cell cycle progression, and glutamine deprivation leads to cell cycle arrest in the S-phase in certain cellular contexts (Fontenelle and Henderson, 1969; Gaglio et al., 2009).”

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• cites Gaglio et al., 2009 sourceNot checked yet

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Majority of proliferating cells in culture require exogenous glutamine.

“Despite the existence of a glutamine biosynthetic pathway in mammalian cells, the majority of proliferating cells in culture require an exogenous supply of glutamine.”

Brain tumor types including primary glioblastomas and brain metastases assimilate exogenous acetate and incorporate acetate-derived carbons into de novo synthesized fatty acids.

“Specifically, a variety of tumor types localized to the brain, including primary glioblastomas as well as brain metastases that originated from other tissues, have been shown to assimilate exogenous acetate and incorporate acetate-derived carbons into de novo synthesized fatty acids (Comerford et al., 2014; Mashimo et al., 2014; Schug et al., 2015).”

• cites Comerford et al., 2014 sourceNot checked yet

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• cites Mashimo et al., 2014 sourceNot checked yet

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• cites Schug et al., 2015 sourceNot checked yet

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Glutamine levels are rate-limiting for cell cycle progression.

“Accordingly, glutamine levels have been shown to be rate-limiting for cell cycle progression, and glutamine deprivation leads to cell cycle arrest in the S-phase in certain cellular contexts (Fontenelle and Henderson, 1969; Gaglio et al., 2009).”

• cites Fontenelle and Henderson, 1969Not checked yet

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• cites Gaglio et al., 2009 sourceNot checked yet

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Amide group of glutamine is indispensable donor of nitrogen for purine and pyrimidine biosynthesis.

“The amide group of glutamine is an indispensable donor of nitrogen for the biosynthesis of purine and pyrimidine bases (Figure 5).”

Some cell types, such as embryonic stem cells and luminal breast cancer cells, can proliferate without glutamine in culture medium, indicating de novo glutamine production in some contexts.

“Interestingly, some cell types, such as embryonic stem cells and luminal breast cancer cells, are capable of proliferating in the absence of glutamine in the culture medium, indicating that in some cellular contexts, glutamine can be produced de novo (Carey et al., 2015; Kung et al., 2011).”

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• cites Kung et al., 2011 sourceNot checked yet

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De novo cholesterol biosynthesis from malonyl-CoA plays a role in tumorigenesis.

“In addition to fatty acid production, the de novo biosynthesis of cholesterol from malonyl-CoA plays a role in tumorigenesis as well.”

• cites Freed-Pastor et al., 2012 sourceNot checked yet

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Aspartate biosynthesis is critically dependent on a cell's ability to conduct oxidative phosphorylation.

“In fact, aspartate biosynthesis has recently been shown to be critically dependent upon a cell’s ability to conduct oxidative phosphorylation (Birsoy et al., 2015; Sullivan et al., 2015).”

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• cites Sullivan et al., 2015 sourceNot checked yet

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Upregulation of ACSS2 may allow cells to recycle acetate released from deacetylation of histones and other cellular proteins.

“Furthermore, upregulation of ACSS2 may potentially allow cells to recycle acetate released from deacetylation of histones and other cellular proteins as well.”

Extracellular acetate is utilized by some cancers as source of acetyl-CoA for biosynthesis.

“Finally, extracellular acetate has recently been shown to be utilized by some cancers as a source of acetyl-CoA for biosynthesis.”

• cites Comerford et al., 2014 sourceNot checked yet

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• cites Mashimo et al., 2014 sourceNot checked yet

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• cites Schug et al., 2015 sourceNot checked yet

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TCA cycle provides metabolic precursors for biosynthesis of non-essential amino acids including aspartate and asparagine.

“In addition to supplying citrate, the TCA cycle also provides metabolic precursors for the biosynthesis of non-essential amino acids including aspartate and asparagine.”

Depletion of plasma asparagine by recombinant bacterial L-Asparaginase is effective anticancer intervention for acute lymphoblastic leukemia.

“Depletion of plasma asparagine by a recombinant form of bacterial L-Asparaginase is an effective anticancer intervention for this cancer type (Hill et al., 1967; Pieters et al., 2011).”

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• cites Pieters et al., 2011 sourceNot checked yet

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α-ketoglutarate may provide citrate for de novo lipogenesis when hypoxia or oncogenic contexts create deficit of glucose-derived acetyl-CoA.

“Finally, α-ketoglutarate may provide a source of citrate for the de novo lipogenesis in a setting in which hypoxia or certain oncogenic contexts create a deficit of glucose-derived acetyl-CoA.”

Glutamine-derived glutamate serves as nitrogen donor for production of non-essential amino acids via transamination.

“Glutamine-derived glutamate serves as a donor of nitrogen for the production of a number of non-essential amino acids via transamination.”

Other c-myc targets involved in nucleotide biosynthesis are TS, IMPDH1, and IMPDH2.

“Other targets of c-myc that are involved in nucleotide biosynthesis are thymidylate synthase (TS) and inosine monophosphate dehydrogenase 1 (IMPDH1) and 2 (IMPDH2) (Liu et al., 2008; Mannava et al., 2008).”

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• cites Mannava et al., 2008 sourceNot checked yet

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Growth signaling elevates cellular demand for reduced nitrogen.

“In addition to increasing the consumption of carbon in biosynthetic pathways, growth signaling concomitantly elevates the cellular demand for reduced nitrogen.”

Most proliferating cells depend on continuous glutamine supply to maintain integrity of TCA cycle intermediates.

“Most proliferating cells depend on a continuous supply of glutamine to maintain the integrity of TCA cycle intermediates (DeBerardinis et al., 2007).”

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Human glioblastoma samples implanted into immunocompromised mouse brains accumulate glutamine relative to normal brain tissue.

“In addition, human glioblastoma samples implanted directly into the brains of immunocompromised mice were found to accumulate glutamine relative to the normal brain tissue (Marin-Valencia et al., 2012);”

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Glutamine is a key structural building block in nucleotide biosynthesis.

“Thus, glutamine is a key structural building block in the biosynthesis of nucleotides.”

Histone and DNA methylation is sensitive to alterations in SAM levels.

“A number of recent reports demonstrate that histone and DNA methylation is sensitive to alterations in SAM levels (Chiang et al., 2009; Shyh-Chang et al., 2013; Towbin et al., 2012).”

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• cites Shyh-Chang et al., 2013 sourceNot checked yet

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• cites Towbin et al., 2012 sourceNot checked yet

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p300 histone acetyltransferase utilizes crotonyl-CoA as substrate.

“In addition to acetyl-CoA, a p300 histone acetyltransferase has recently been shown to utilize crotonyl-CoA as a substrate as well.”

• cites Sabari et al., 2015 sourceNot checked yet

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Meta-analysis identified PYCR1 as one of the most commonly overexpressed genes in tumors.

“In fact, a meta-analysis of metabolic enzyme expression across diverse tumor types identified PYCR1 as one of the most commonly overexpressed genes in tumors (Nilsson et al., 2014).”

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2-HG acts as competitive inhibitor of α-ketoglutarate-dependent dioxygenases due to structural similarity to α-ketoglutarate.

“Owing to its structural similarity to α-ketoglutarate, 2-HG acts as a competitive inhibitor of α-ketoglutarate-dependent dioxygenases (Xu et al., 2011).”

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Reduced expression of ASS1 and ASL is associated with poor prognosis and resistance to chemotherapy.

“Reduced expression of ASS1 and ASL are associated with poor prognosis and resistance to chemotherapy (McAlpine et al., 2014; Nicholson et al., 2009).”

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• cites Nicholson et al., 2009 sourceNot checked yet

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IDH1 and IDH2 mutations identified in low-grade glioma, chondrosarcoma, cholangiocarcinoma, and AML.

“IDH1 and IDH2 mutations have been identified in low-grade glioma, where they represent a likely initiator lesion, as well as in chondrosarcoma, cholangiocarcinoma, and acute myeloid leukemia (AML) (Balss et al., 2008; Borger et al., 2012; Cohen et al., 2013; Mardis et al., 2009; Parsons et al., 2008; Paschka et al., 2010).”

• cites Balss et al., 2008 sourceNot checked yet

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• cites Borger et al., 2012 sourceNot checked yet

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• cites Cohen et al., 2013 sourceNot checked yet

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Activated Akt expands extramitochondrial acetyl-CoA pool by activating ACLY.

“Activated Akt expands the extramitochondrial pool of acetyl-CoA by activating ACLY, which converts cytosolic citrate into acetyl-CoA and oxaloacetate.”

Cytosolic acetyl-CoA builds up when cells metabolize more glucose than needed for bioenergetic support.

“A key metabolite that builds up when cells metabolize more glucose than needed for bioenergetic support is cytosolic acetyl-CoA.”

α-ketoglutarate-dependent dioxygenases are prone to inhibition by succinate and fumarate.

“In addition, α-ketoglutarate-dependent dioxygenases are prone to the inhibition by their reaction product, succinate, as well as by fumarate, the downstream product of succinate degradation in the TCA cycle.”

Glucose- and oncogene-driven increases in global histone acetylation are blocked by ACLY inhibition.

“Furthermore, studies have shown that both the glucose- and oncogene-driven increases in global histone acetylation are blocked by ACLY inhibition (Lee et al., 2014; Wellen et al., 2009).”

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• cites Wellen et al., 2009 sourceNot checked yet

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Deposition of crotonyl marks on select histone tail residues activates gene expression more potently than acetyl marks.

“Notably, deposition of crotonyl marks on select amino acid residues within histone tails was found to activate gene expression even more potently than acetyl marks (Sabari et al., 2015).”

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Mutant IDH1 and IDH2 exhibit neomorphic function converting α-ketoglutarate to D-2-hydroxyglutarate.

“In contrast to wild-type isocitrate dehydrogenases, which convert the TCA cycle metabolite isocitrate to α-ketoglutarate, a mutant form of IDH prefers to use α-ketoglutarate as a substrate, catalyzing its conversion to the D-enantiomer of 2-hydroxyglutarate (2-HG) (Dang et al., 2010; Ward et al., 2010).”

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• cites Ward et al., 2010 sourceNot checked yet

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Another possible reason for arginine auxotrophy in cancer may be that suppression of ASS1-driven argininosuccinate production leads to aspartate accumulation for nucleotide biosynthesis.

“Another possible reason for arginine auxotrophy in cancer may be related to the fact that the suppression of ASS1-driven argininosuccinate production leads to an accumulation of its substrate aspartate, which can then be applied toward nucleotide biosynthesis.”

Wide variety of post-translational modifications are carried out by α-ketoglutarate-dependent dioxygenases.

“A wide variety of post-translational modifications in the cell are carried out by the members of a large class of α-ketoglutarate-dependent dioxygenases.”

Cytosolic acetyl-CoA is obligate substrate for enzymes that acetylate histones and other proteins.

“Cytosolic acetyl-CoA is the obligate substrate for enzymes that acetylate histones and other proteins.”

Crotonyl-CoA can be produced from catabolism of lysine, tryptophan, and butyrate.

“Crotonyl-CoA can be produced from the catabolism of lysine and tryptophan, as well as of a short-chain fatty acid butyrate.”

Metabolic networks are not merely passive recipients of growth signals but directly transmit information about cellular metabolic state to regulatory enzymes including those mediating epigenetic marks.

“However, metabolic networks themselves are not merely passive recipients of growth signals, but quite the contrary, directly transmit the information about the cellular metabolic state to a diverse array of regulatory enzymes, among which are those that mediate the deposition and removal of epigenetic marks from chromatin (Katada et al., 2012)(Figure 6).”

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Gain-of-function mutations of IDH1 and IDH2 modulate activity of α-ketoglutarate-dependent dioxygenases.

“Another prominent class of tumor-associated genetic alterations that modulate the activity of α-ketoglutarate-dependent dioxygenases are gain-of-function mutations of isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2).”

IDH-driven gliomas, leukemias, and chondrosarcomas display prominent CpG island hypermethylation reminiscent of SDH- and FH-deficient cancers.

“Indeed, IDH-driven gliomas, leukemias and chondrosarcomas display a prominent CpG island hypermethylation, reminiscent of the hypermethylator phenotype seen in SDH- and FH-deficient cancers (Figueroa et al., 2010; Lu et al., 2013; Turcan et al., 2012).”

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• cites Lu et al., 2013Not checked yet

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• cites Turcan et al., 2012 sourceNot checked yet

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Similarly to carbon, nitrogen metabolism undergoes complex reprogramming in tumorigenesis.

“Taken together, while this area of cancer metabolism remains under active investigation, it is clear that similarly to carbon, the metabolism of nitrogen undergoes complex reprogramming in tumorigenesis.”

Numerous methylation reactions including histone, DNA, and mRNA methylation utilize SAM as methyl donor.

“Numerous methylation reactions in the cell, including the deposition of methyl marks on histone tails, cytosine methylation on DNA and adenosine methylation on mRNA utilize S-adenosylmethionine (SAM) as a donor of methyl groups.”

POX expression inhibits tumor cell growth by triggering G2 cell cycle arrest.

“Expression of POX has been shown to inhibit tumor cell growth by triggering cell cycle arrest in the G2 phase (Liu et al., 2009).”

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Sensitive to NAD+ or FAD availability, these enzymes orchestrate global post-translational and epigenetic changes that promote energy conservation.

“Sensitive to changes in NAD+ or FAD availability, these enzymes orchestrate global post-translational and epigenetic changes that promote energy conservation (Hino et al., 2012; Schwer and Verdin, 2008).”

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• cites Schwer and Verdin, 2008Not checked yet

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PYCR1 expression is upregulated by c-myc.

“The expression of the principal enzyme in proline biosynthesis, pyrroline-5-carboxylate reductase (PYCR1), is upregulated by c-myc (Liu et al., 2012).”

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Reaction mechanism of α-ketoglutarate-dependent dioxygenases involves concurrent oxidation of α-ketoglutarate into succinate.

“The reaction mechanism of α-ketoglutarate-dependent dioxygenases involves a concurrent oxidation of a co-substrate α-ketoglutarate into succinate.”

Arginine auxotrophy of tumors is being exploited in development of anticancer therapies.

“Accordingly, the auxotrophy of tumors for arginine is being exploited in the development of anticancer therapies (Delage et al., 2010).”

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c-myc-orchestrated remodeling of non-essential amino acid metabolism involves proline metabolism.

“In addition to its effects on glutamine metabolism, c-myc-orchestrated remodeling of non-essential amino acid metabolism involves the metabolism of proline (Phang et al., 2008).”

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Histone acetylation is exquisitely sensitive to alterations in cellular nutritional and signaling status.

“Histone acetylation is exquisitely sensitive to alterations in the cellular nutritional and signaling status (Cai et al., 2011; Shi and Tu, 2013).”

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• cites Shi and Tu, 2013 sourceNot checked yet

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Immunohistochemical analysis of glioblastoma and prostate tumor samples shows Akt activation levels closely correlate with global histone acetylation status.

“Immunohistochemical analysis of glioblastoma and prostate tumor samples has shown that Akt activation levels closely correlate with global histone acetylation status (Lee et al., 2014).”

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Biallelic loss of SDH found in familial paragangliomas and pheochromocytomas and in a subset of sporadic GIST creates succinate build-up.

“For instance, a biallelic loss of succinate dehydrogenase (SDH), an alteration found in familial paragangliomas and pheochromocytomas, as well as in a subset of sporadic gastrointestinal stromal tumors, creates a build-up of succinate (Astuti et al., 2001; Janeway et al., 2011).”

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• cites Janeway et al., 2011 sourceNot checked yet

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Large variety of novel histone marks, such as formylation, propionylation, butyrylation, malonylation, and succinylation, have been identified by tandem mass spectrometry.

“In fact, a large variety of novel histone marks, such as formylation, propionylation, butyrylation, malonylation and succinylation have recently been identified by tandem mass spectrometry (Chen et al., 2007; Wisniewski et al., 2008; Xie et al., 2012).”

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• cites Wisniewski et al., 2008 sourceNot checked yet

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• cites Xie et al., 2012 sourceNot checked yet

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Aberrantly activated growth and survival signals that drive tumorigenesis facilitate reprogramming of cancer cell metabolism to enable increased nutrient acquisition and biosynthesis.

“Aberrantly activated growth and survival signals that drive tumorigenesis facilitate the reprogramming of cancer cell metabolism to enable increased nutrient acquisition and biosynthesis.”

Intracellular α-ketoglutarate levels can directly influence activity of α-ketoglutarate-dependent dioxygenases.

“Accordingly, intracellular levels of α-ketoglutarate can directly influence the activity of these enzymes.”

ASS1 and ASL are frequently epigenetically silenced in melanoma, renal cell carcinoma, and hepatocellular carcinoma.

“Intriguingly, both ASS1 and ASL enzymes are frequently epigenetically silenced in melanoma, renal cell carcinoma and hepatocellular carcinoma (Bowles et al., 2008; Ensor et al., 2002; Yoon et al., 2007).”

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• cites Ensor et al., 2002Not checked yet

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• cites Yoon et al., 2007 sourceNot checked yet

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Removal of acetyl and methyl marks is guided by cellular metabolic state.

“The removal of acetyl and methyl marks is also guided by the cellular metabolic state.”

HIF1α elevation in context of SDH loss can be reversed by addition of membrane-permeable α-ketoglutarate.

“In fact, the latter, at least in the context of SDH loss, can be reversed by the addition of a membrane-permeable form of α-ketoglutarate (MacKenzie et al., 2007).”

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High dietary choline intake is linked to a significantly increased risk of lethal prostate cancer.

“High dietary intake of choline has been linked to a significantly increased risk of lethal prostate cancer (Richman et al., 2012).”

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Lactate secretion through MCT1 is coupled to H+ co-transport, causing acidification of the cellular microenvironment.

“The secretion of lactate into the extracellular space via the monocarboxylate transporter MCT1 is coupled to the co-transport of H+, which causes acidification of the cellular microenvironment.”

Small molecule inhibition of mutant IDH1 in glioma and IDH2 in leukemia promotes differentiation.

“Conversely, small molecule-mediated inhibition of mutant IDH1 in glioma and IDH2 in leukemia markedly promoted differentiation in these contexts (Rohle et al., 2013; Wang et al., 2013).”

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• cites Wang et al., 2013 sourceNot checked yet

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Cysteine is the second most depleted amino acid in pancreatic tumors compared with normal pancreatic tissue.

“Consistent with its heavy utilization by cancer cells, cysteine was found to be the second most depleted amino acid in pancreatic tumors in comparison to normal pancreatic tissue (Kamphorst et al., 2015).”

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The xCT transporter exports at least 30% of glutamine taken up by cells as glutamate, exchanging it for cysteine.

“In fact, no less than 30% of imported glutamine was shown to leave the cell through the xCT transporter as glutamate, while being exchanged for cysteine (Collins et al., 1998).”

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Carbonic anhydrase expression, especially the CAIX isoform, increases during hypoxia.

“Expression of carbonic anhydrases, in particular the CAIX isoform, is elevated during hypoxia (Svastova et al., 2004).”

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Conditions in the tumor microenvironment strongly affect cancer cell metabolism.

“Reciprocally, the conditions within the tumor microenvironment have profound effects on the metabolism of a cancer cell.”

L-2-HG is implicated as metabolic mediator of cellular stress response to hypoxia.

“Furthermore, L-2-HG levels were found to increase in response to hypoxia as a result of promiscuous substrate use by LDH-A and malate dehydrogenase (MDH) (Intlekofer et al., 2015), and two recent studies implicate L-2-HG as a metabolic mediator of the cellular stress response to hypoxia (Intlekofer et al., 2015; Oldham et al., 2015).”

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• cites Oldham et al., 2015 sourceNot checked yet

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CO2 produced by mitochondrial decarboxylation diffuses out of cells and is converted by extracellular carbonic anhydrases into H+ and HCO3−, contributing to extracellular acidification.

“In addition, the surplus of CO2 generated in mitochondrial decarboxylation reactions contributes to the extracellular acidification as well. To this end, CO2 diffuses into the extracellular space, where it becomes converted to H+ and HCO3− by a class of extracellular carbonic anhydrases (Swietach et al., 2007).”

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High consumption of extracellular glucose and glutamine by cancer cells leads to extracellular lactate accumulation.

“The high utilization of extracellular glucose and glutamine by cancer cells results in the accumulation of extracellular lactate, which was shown to affect a number of cell types within the tumor microenvironment.”

2-HG abundance has been used for 1H magnetic resonance spectroscopy-based imaging of IDH-mutant gliomas.

“The abundance of 2-HG has been utilized for 1H magnetic resonance spectroscopy-based imaging of IDH-mutant gliomas (Choi et al., 2012).”

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A diet high in choline and betaine is associated with decreased breast and lung cancer risk.

“In contrast, a diet high in choline and betaine was associated with a decreased breast and lung cancer risk (Xu et al., 2009a; Ying et al., 2013; Zhang et al., 2013).”

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• cites Ying et al., 2013 sourceNot checked yet

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• cites Zhang et al., 2013 sourceNot checked yet

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Proliferating cancer cells change the metabolic composition of the extracellular space around them.

“In addition to these inputs, proliferating cancer cells alter the metabolic composition of the extracellular milieu around them as well (Figure 7).”

Choline and its derivative betaine can serve as methyl-group donors for SAM production.

“Two other dietary compounds that can be utilized as donors of methyl groups for SAM production are choline and its derivative betaine.”

Small molecule inhibitors of IDH1 and IDH2 have been reported to induce remissions in phase I clinical trials for AML patients with respective mutations.

“Moreover, small molecule inhibitors of IDH1 and IDH2 have been reported to induce remissions in phase I clinical trials for treatment of AML patients with the respective mutations.”

Multiple lines of evidence suggest that sulfur metabolism may be reprogrammed in cancer.

“For instance, multiple lines of evidence indicate that the metabolism of sulfur may undergo reprogramming in cancer.”

Kynurenine that accumulates can bind the aryl hydrocarbon receptor (AhR) as a ligand.

“Furthermore, accumulated kynurenine acts as a ligand for aryl hydrocarbon receptor (AhR) (Opitz et al., 2011).”

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Lactate accumulation promotes angiogenesis.

“Furthermore, lactate accumulation is instrumental for the promotion of angiogenesis.”

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• cites Schmid et al., 2007 sourceNot checked yet

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• cites Sonveaux et al., 2012 sourceNot checked yet

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In proliferating cells, cysteine is used for biosynthesis of glutathione, iron-sulfur clusters, and hydrogen sulfide (H2S).

“Cysteine has several metabolic fates in proliferating cells, among which are the biosynthesis of glutathione and iron-sulfur clusters, as well as of hydrogen sulfide (H2S)”

Some tumor types display elevations in 2-HG even without IDH mutations.

“Notably, some tumor types display elevations in 2-HG even in the absence of IDH mutations.”

Reciprocal interactions between cancer cells and their microenvironment create selective pressure that reshapes cancer cell metabolism and promotes a more aggressive state.

“Taken together, reciprocal interactions between cancer cells and their microenvironment impose a selective pressure that further shapes cancer cell metabolism and actively contributes to the emergence of a more aggressive state.”

Knock-in of mutant IDH1 allele into normal hematopoietic cells and chondrocytes in vivo triggers aberrant expansion of targeted cell lineages.

“Furthermore, a knock-in of a mutant IDH1 allele into normal hematopoietic cells and into chondrocytes in vivo triggers an aberrant expansion of targeted cell lineages (Hirata et al., 2015; Sasaki et al., 2012).”

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• cites Sasaki et al., 2012 sourceNot checked yet

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L-2-HG levels increase in response to hypoxia due to promiscuous substrate use by LDH-A and MDH.

“Furthermore, L-2-HG levels were found to increase in response to hypoxia as a result of promiscuous substrate use by LDH-A and malate dehydrogenase (MDH) (Intlekofer et al., 2015), and two recent studies implicate L-2-HG as a metabolic mediator of the cellular stress response to hypoxia (Intlekofer et al., 2015; Oldham et al., 2015).”

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• cites Oldham et al., 2015 sourceNot checked yet

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Diets deficient in choline and betaine directly affect histone and DNA methylation in several animal models.

“Furthermore, diets deficient in choline and betaine were shown to directly affect histone and DNA methylation in a number animal models (Du et al., 2009; Mehedint et al., 2010; Niculescu et al., 2006), suggesting that alterations in exogenous methyl donor availability may have strong effects on cellular epigenetic state and thus contribute to tumorigenesis.”

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• cites Mehedint et al., 2010 sourceNot checked yet

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• cites Niculescu et al., 2006 sourceNot checked yet

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Multiple non-malignant cell types near a tumor-including fibroblasts, endothelial cells, and immune cells-show characteristic phenotypic changes when they reside close to a growing tumor.

“a variety of genetically stable cell types, among which are tumor-associated fibroblasts, endothelial cells, as well as innate and adaptive immune system components, are known to undergo characteristic phenotypic changes as a consequence of residing in the vicinity of a growing tumor (Hanahan and Coussens, 2012).”

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Loss of tryptophan causes effector T cells to undergo apoptosis linked to amino acid deprivation.

“As a consequence, tryptophan depletion triggers amino acid deprivation-associated apoptosis of effector T cells (Fallarino et al., 2002).”

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In mice, colon cancer xenografts grow less when serine and glycine are absent from the diet.

“Indeed, dietary serine and glycine deficiency has been shown to impair xenograft growth of colon cancer cells in mice (Maddocks et al., 2013).”

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Elevated 2-HG levels have been detected in triple-negative breast cancer.

“For instance, elevated 2-HG levels have been detected in triple-negative breast cancer (Terunuma et al., 2014).”

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The study of cancer metabolism is revealing new principles of how anabolic metabolism supports normal cell growth, proliferation, and differentiation.

“Furthermore, the study of cancer metabolism is not only shedding light on carcinogenesis but is also revealing new principles of how the biochemistry of anabolic metabolism is orchestrated to support normal cell growth, proliferation, and differentiation.”

Copper levels can be elevated 2-3 fold in breast and ovarian tumors and in leukemia.

“Copper levels in particular can be elevated as much as 2–3 fold in breast and ovarian tumors, as well as in leukemia (Gupte and Mumper, 2009).”

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Ascorbic acid treatment affects DNA methylation in embryonic stem cells and mouse embryonic fibroblasts in a TET2-dependent manner.

“Notably, ascorbic acid treatment was shown to affect DNA methylation in embryonic stem cells and mouse embryonic fibroblasts in a manner that is dependent on TET2 (Blaschke et al., 2013; Minor et al., 2013).”

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• cites Minor et al., 2013 sourceNot checked yet

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Levels of some trace metals, such as zinc and copper, differ between cancer cells and normal tissue.

“Furthermore, levels of select trace metals, such as zinc and copper, are altered in cancer cells compared to the normal tissue.”

Alterations in exogenous methyl donor availability may strongly affect cellular epigenetic state and thereby contribute to tumorigenesis.

“suggesting that alterations in exogenous methyl donor availability may have strong effects on cellular epigenetic state and thus contribute to tumorigenesis.”

• AssumptionRests on an assumption: Findings from animal models about dietary methyl donors and epigenetic marks apply to human tumorigenesis.