The Emerging Hallmarks of Cancer Metabolism

In the paper

“Increased lactate levels promote the emergence of an immune-permissive microenvironment by attenuating dendritic and T cell activation and monocyte migration (Fischer et al., 2007; Goetze et al., 2011; Gottfried et al., 2006).”

What the sources say

• Partly supported

  The Discussion reports that lactic acid suppresses human cytotoxic T-cell functions and says earlier work found altered antigen presentation by monocyte-derived dendritic cells. Our copy does not establish reduced dendritic-cell activation or impaired monocyte migration. It also distinguishes lactic acid from sodium lactate, which did not suppress T-cell functions. (LLM, conf=0.88)

  cites Fischer et al., 2007 sourceExperimental — accuracy not yet measured
• Not checked yetcites Goetze et al., 2011
• Partly supported

  The Discussion reports that lactic acid inhibits dendritic-cell antigen presentation and reduces IL-12 secretion; the section on phenotypical characterization reports concentration-dependent inhibition of T-cell proliferation during stimulation by dendritic cells. These findings support an immune-suppressive effect, but our copy does not establish that lactate impairs monocyte migration. Its figure on monocyte infiltration does not attribute an impairment to lactate. (LLM, conf=0.88)

  cites Gottfried et al., 2006 sourceExperimental — accuracy not yet measured

In the paper

“This observation has been confirmed in a variety of tumor contexts and shown to correlate with poor tumor prognosis”

What the sources say

• Not checked yetcites Som et al., 1980

In the paper

“tumorigenesis-associated metabolic alterations encompass all stages of cell-metabolite interaction, (a) affecting the metabolite influx through conferring an increased ability to acquire the necessary nutrients; (b) shaping the way the nutrients are preferentially assigned to metabolic pathways that contribute to cellular tumorigenic properties, as well as (c) exerting long-ranging effects on”

In the paper

“Normally, despite being surrounded by nutrient-rich plasma and the extracellular fluid, metazoan cells do not import nutrients in a constitutive manner. On the contrary, nutrient uptake is strictly regulated by growth factor signaling”

What the sources say

• Not checked yetcites Thompson, 2011 source

In the paper

“controlled oxidation of carbon skeletons of glucose and glutamine allows a cell to capture their reducing power either in the form of NADH and FADH2, which mediate the transfer of electrons to the electron transport chain to fuel ATP generation, or in the form of a related cofactor NADPH, which provides reducing power for a wide variety of biosynthetic reactions, as well as helps maintain cellular”

In the paper

“Positron emission tomography (PET)-based imaging of the uptake of a radioactive fluorine-labeled glucose analog, 18F-fluorodeoxyglucose (18F-FDG) has been successfully used in the clinic for tumor diagnosis and staging, as well as for monitoring responsiveness to treatment”

What the sources say

• Not checked yetcites Almuhaideb et al., 2011

In the paper

“This, in turn, negatively affects cell size, mitochondrial potential and ATP generation – all despite the abundance of glucose in the culture medium”

What the sources say

• Not checked yetcites Rathmell et al., 2000

In the paper

“In order to fulfill the biosynthetic demands associated with proliferation, a cell must increase the import of nutrients from the environment.”

In the paper

“Two principal nutrients that support survival and biosynthesis in mammalian cells are glucose and glutamine.”

In the paper

“mTORC1 inhibitors greatly increase the cellular ability to recover amino acids from captured extracellular protein and enhance their growth in the absence of essential amino acids”

What the sources say

• Not checked yetcites Palm et al., 2015

In the paper

“free amino acids can be recovered from the engulfment and digestion of entire living cells via a process known as entosis (Figure 3B), as well as from phagocytosis of apoptotic cellular corpses”

What the sources say

• Not checked yetcites Krajcovic et al., 2013 source
• Not checked yetcites Stolzing and Grune, 2004

In the paper

“c-myc induces the transcription of glutamine transporters ASCT2 and SN2, and in addition, promotes expression of glutamine-utilizing enzymes glutaminase (GLS1), phosphoribosyl pyrophosphate synthetase (PRPS2) and carbamoyl-phosphate synthetase 2 (CAD)”

What the sources say

• Not checked yetcites Eberhardy and Farnham, 2001
• Not checked yetcites Gao et al., 2009 source
• Not checked yetcites Mannava et al., 2008

In the paper

“While rapamycin suppresses cancer cell proliferation at the tumor margin where the vascular delivery of nutrients is effective, rapamycin enhances cell proliferation within the poorly-vascularized tumor core by promoting enhanced lysosomal degradation of extracellular proteins”

What the sources say

• Not checked yetcites Palm et al., 2015

In the paper

“subsequent investigations into the mitochondrial status of tumor cells have shown that by and large, tumor cells possess functional mitochondria and retain the ability to conduct oxidative phosphorylation.”

In the paper

“Thus, KRAS-mutant cells may not only have a nutritional advantage over their non-mutant neighbors, but also actively eliminate the latter.”

In the paper

“exogenous expression of a constitutively active form of Akt alone can stimulate glycolysis and is sufficient to restore cell size, viability, mitochondrial potential and ATP levels in growth factor-deprived cells in a manner that is dependent upon the presence of glucose in the culture medium”

What the sources say

• Not checked yetcites Plas et al., 2001
• Not checked yetcites Rathmell et al., 2003 source

In the paper

“These observations suggest that, rather than being an adaptation to a defect in respiration, the Warburg effect is a regulated metabolic state and may, in fact, be beneficial during a time of increased biosynthetic demand.”

In the paper

“Culturing mammary epithelial cells under conditions where the cells are detached from the extracellular matrix compromises glucose uptake and results in a depressed mitochondrial potential and decreased ATP levels”

What the sources say

• Not checked yetcites Grassian et al., 2011
• Not checked yetcites Schafer et al., 2009 source

In the paper

“Akt potentiates the activity of the hexokinase (HK), which phosphorylates glucose molecules, thus preventing their efflux back into the extracellular space, as well as of the phosphofructokinase (PFK) enzyme, which catalyzes the key irreversible step of glycolysis”

What the sources say

• Not checked yetcites Deprez et al., 1997
• Not checked yetcites Gottlob et al., 2001

In the paper

“Other oncogenic signaling proteins - notably, Ras, have been found to upregulate GLUT1 mRNA expression and increase cellular glucose consumption”

What the sources say

• Not checked yetcites Murakami et al., 1992

In the paper

“Thus, the utilization of extracellular protein as nutrients is repressed by mTORC1 under amino acid-replete conditions and is only utilized as an emergency source in conditions when free amino acids are insufficient.”

In the paper

“generation of palmitic acid consumes 14 reducing equivalents, while building a cholesterol molecule requires 26”

What the sources say

• Not checked yetcites Lunt and Vander Heiden, 2011 source

In the paper

“the 18F-FDG-PET signal intensity in tumors correlates closely with the level of PI3K/Akt pathway activity, and is attenuated by PI-3 kinase and receptor tyrosine kinase inhibitors”

What the sources say

• Not checked yetcites Benz et al., 2011
• Not checked yetcites Lheureux et al., 2013
• Not checked yetcites Ma et al., 2009

In the paper

“In contrast to the effect of KRASG12D, PI3K/Akt signaling does not promote cellular utilization of extracellular protein, despite the ability of this pathway to stimulate the uptake of low molecular weight nutrients”

What the sources say

• Not checked yetcites Palm et al., 2015

In the paper

“PI3K/Akt signaling promotes both the expression of glucose transporter GLUT1 mRNA and the translocation of GLUT1 protein from the endomembranes to the cell surface”

What the sources say

• Not checked yetcites Barthel et al., 1999
• Not checked yetcites Wieman et al., 2007

In the paper

“A designated donor of reducing equivalents that is used in cellular biosynthetic reactions is NADPH.”

In the paper

“A first committed step of hexosamine biosynthesis is a glutamine fructose-6-phospate aminotransferase 1 (GFPT1)-catalyzed production of glucosamine-6-phosphate from fructose-6-phosphate and glutamine.”

In the paper

“A rate-limiting serine biosynthesis enzyme, 3-phosphoglycerate dehydrogenase (PHGDH), is frequently focally amplified in breast cancer and melanoma and is required for the growth of PHGDH-amplified cells in vitro as well as in vivo”

What the sources say

• Not checked yetcites Locasale et al., 2011 source
• Not checked yetcites Possemato et al., 2011 source

In the paper

“In contrast to the proliferating bulk of a tumor, accumulating evidence suggests that quiescent subpopulations of tumor cells are markedly less glycolytic and exhibit higher dependence on oxidative phosphorylation, as well as elevated expression of mitochondrial respiratory components.”

What the sources say

• Not checked yetcites LeBleu et al., 2014
• Not checked yetcites Viale et al., 2014 source

In the paper

“glycolytic intermediates leave glycolysis to take part in diverse biosynthetic reactions; accordingly, the rate-limiting enzymes within branching pathways of glycolysis are frequently upregulated in tumors.”

In the paper

“While the de novo biosynthesis of fatty acids is low in normal adult tissues – with the exception of lipogenic tissues such as liver, adipose tissue or mammary epithelium in the period of lactation, tumorigenesis is associated with a dramatic increase in lipid production (Li and Cheng, 2014; Menendez and Lupu, 2007).”

What the sources say

• Not checked yetcites Li and Cheng, 2014
• Not checked yetcites Menendez and Lupu, 2007

In the paper

“By using FAD as an electron acceptor, the mGPDH-catalyzed reaction reduces net mitochondrial electrical chemical potential from NADH generated via glycolysis.”

In the paper

“Furthermore, increased ROS levels facilitate the activation of HIF1α and NRF2 transcription factors, thus promoting transcriptional programs that further contribute to tumorigenesis (Bertout et al., 2008; Sporn and Liby, 2012).”

What the sources say

• Not checked yetcites Bertout et al., 2008
• Not checked yetcites Sporn and Liby, 2012 source

In the paper

“First in the series of these branching pathways is the pentose phosphate pathway (PPP), in which glucose-6-phosphate becomes partially oxidized to generate NADPH and ribose-5-phosphate – a structural component of nucleotides.”

In the paper

“By converting excess pyruvate to lactate, proliferating cells prevent accumulation of cytosolic NADH and reduce ATP production promoting continued cytosolic glucose metabolism free from feedback repression by excess mitochondrial ATP generation.”

In the paper

“The key enzymes in the pathway, transketolase-like 1 (TKTL1) and transaldolase (TALDO) are frequently overexpressed in cancer”

What the sources say

• Not checked yetcites Wang et al., 2011a
• Not checked yetcites Xu et al., 2009b

In the paper

“This step is regulated by pyruvate kinase (PK), an enzyme that converts phosphoenolpyruvate to the final product of glycolysis, pyruvate.”

In the paper

“Any excess glycolytic flux not utilized for biosynthesis is preferentially converted to lactate to help preserve a sufficient pool of NAD+ to sustain glycolysis and avoid flooding the mitochondria with a supply of NADH that would suppress the TCA cycle.”

In the paper

“To this end, ROS act as inhibitors of protein phosphatases such as PTEN and PTP1B, as well as activators of Src family kinases and MAPK (Denu and Tanner, 1998; Kamata et al., 2005; Lee et al., 2002; Yan and Berton, 1996).”

What the sources say

• Not checked yetcites Denu and Tanner, 1998
• Not checked yetcites Kamata et al., 2005 source
• Not checked yetcites Lee et al., 2002

In the paper

“DHAP is converted by glycerol-3-phosphate dehydrogenase 1 (GPD1) into glycerol-3-phosphate, which is utilized in the biosynthesis of diverse phospholipids, a major structural component of cellular membranes.”

In the paper

“wild-type, but not the mutant, p53 inhibits PPP by directly binding and inactivating the rate-limiting PPP enzyme glucose-6-phosphate dehydrogenase (G6PD)”

What the sources say

• Not checked yetcites Jiang et al., 2011

In the paper

“Thus, PKM2 is inhibited by tyrosine phosphorylation and activated by serine (Chaneton et al., 2012; Christofk et al., 2008b; Ye et al., 2012).”

What the sources say

• Not checked yetcites Chaneton et al., 2012
• Not checked yetcites Christofk et al., 2008b
• Not checked yetcites Ye et al., 2012

In the paper

“While PKM1 is more efficient at producing pyruvate, the majority of proliferating cells and essentially all cancer cells express primarily the PKM2 variant”

What the sources say

• Not checked yetcites Christofk et al., 2008a

In the paper

“Though glycolysis is classically depicted as a single chain of molecular events that leads to the generation of pyruvate, a number of glycolytic intermediates can be diverted into branching pathways, generating diverse biosynthetic precursors.”

In the paper

“Through the generation of N-acetylglucosamine (GlcNAc), a substrate for N- and O-linked glycosylation, the hexosamine pathway provides substrates for cellular glycosylation reactions as well as heparan sulfate and hyaluronic acid biosynthesis, potentiates receptor-mediated signaling and regulates the stability of select proteins, including c-myc”

What the sources say

• Not checked yetcites Itkonen et al., 2013
• Not checked yetcites Spiro, 2002
• Not checked yetcites Wellen et al., 2010

In the paper

“Among such populations are stem-like subclones that emerge following the oncogene ablation in vivo, as well as circulating tumor cells (CTCs) (LeBleu et al., 2014; Viale et al., 2014).”

What the sources say

• Not checked yetcites LeBleu et al., 2014
• Not checked yetcites Viale et al., 2014 source

In the paper

“In support of this paradigm, a reintroduction of the PKM1 isoform compromises cancer cell proliferation and tumorigenesis in vivo, in part by negatively affecting serine-dependent biosynthesis (Ye et al., 2012).”

What the sources say

• Not checked yetcites Ye et al., 2012

In the paper

“while the acetyl-CoA serves as a precursor for lipid biosynthesis and protein acetylation.”

In the paper

“Thus, c-myc not only facilitates glutamine uptake, but also promotes its utilization in the biogenesis of purine and pyrimidine bases.”

In the paper

“Furthermore, activity of CAD enzyme is regulated via phosphorylation by MAPK and by mTORC1-dependent S6 kinase (Ben-Sahra et al., 2013; Graves et al., 2000; Robitaille et al., 2013).”

What the sources say

• Not checked yetcites Ben-Sahra et al., 2013 source
• Not checked yetcites Graves et al., 2000
• Not checked yetcites Robitaille et al., 2013 source

In the paper

“A non-essential amino acid containing two atoms of reduced nitrogen, glutamine serves as the principal way in which reduced nitrogen is transported between cells in metazoan organisms.”

In the paper

“Thus, one glutamine molecule is used in the production of uracil and thymine, cytosine and adenine each require two, and building a guanine base costs a cell three molecules of glutamine.”

In the paper

“In addition to being utilized for nucleotide biosynthesis, glutamine can be directly deamidated to glutamate by glutaminase which is frequently upregulated in cancer cells in a c-myc-dependent manner.”

In the paper

“ASNS is frequently upregulated in tumors and is associated with poor prognosis (Sircar et al., 2012; Zhang et al., 2014).”

What the sources say

• Not checked yetcites Sircar et al., 2012
• Not checked yetcites Zhang et al., 2014 source

In the paper

“Imported acetate is converted to acetyl-CoA in a reaction catalyzed by acetyl-CoA synthetase 2 (ACSS2), which is a target for amplification in breast cancer.”

In the paper

“In fact, all three major components involved in fatty acyl chain biosynthesis – ACLY, ACC and FASN – are frequently upregulated in transformed cells; furthermore, their inhibition reduces tumor cell growth in vitro and in vivo (Chajes et al., 2006; Flavin et al., 2010; Migita et al., 2008; Milgraum et al., 1997).”

What the sources say

• Not checked yetcites Chajes et al., 2006 source
• Not checked yetcites Flavin et al., 2010
• Not checked yetcites Migita et al., 2008 source

In the paper

“These reports highlight that the cell lineage context, as well as potential secondary effects associated with the adaptation of cells to tissue culture conditions may play an important role in the choice of an anaplerotic substrate.”

In the paper

“In a process referred to as reductive carboxylation, a section of the TCA cycle reverses itself, converting α-ketoglutarate into citrate, which can be then used to generate a source of cytosolic acetyl-CoA (Metallo et al., 2012; Wise et al., 2011).”

What the sources say

• Not checked yetcites Metallo et al., 2012 source
• Not checked yetcites Wise et al., 2011 source

In the paper

“Glutamine can be captured in mitochondria by glutaminase and the resulting glutamate converted into α-ketoglutarate by either glutamate dehydrogenase or amino acid transaminases.”

In the paper

“An increased capacity for the producing lipids de novo not only facilitates the formation of lipid bilayers, but also enables a cell to alter its membrane composition in favor of oxidative damage-resistant saturated fatty acids as means of adapting to oxidative stress (Rysman et al., 2010).”

What the sources say

• Not checked yetcites Rysman et al., 2010

In the paper

“A carrier of four nitrogen atoms, arginine serves as a precursor for a wide variety of nitrogenous compounds, among which are polyamines, creatine, agmatine and pyrroline-5-carboxylate, a precursor for the biosynthesis of proline.”

In the paper

“Moreover, PC inhibition in NSCLC-derived cell lines suppresses fatty acid biosynthesis and dramatically reduces proliferation even in the presence of ample glutamine (Sellers et al., 2015).”

What the sources say

• Not checked yetcites Sellers et al., 2015

In the paper

“Thus, hypoxia-associated deficit of acetyl-CoA can be augmented not only through the reductive carboxylation of α-ketoglutarate, but also by increasing the utilization of free acetate from plasma and interstitial fluid.”

In the paper

“In c-myc-transformed cells in particular, glutamine deprivation leads to the collapse of the TCA cycle and triggers cell death, which can be rescued by the addition of oxaloacetate or a membrane-permeable form of α-ketoglutarate (Wise et al., 2008; Yuneva et al., 2007).”

What the sources say

• Not checked yetcites Wise et al., 2008 source
• Not checked yetcites Yuneva et al., 2007 source

In the paper

“Polyamine levels increase in proliferating cells; moreover, polyamines have been shown to inhibit apoptosis and promote tumor growth and invasion (Casero and Marton, 2007; Gerner and Meyskens, 2004).”

What the sources say

• Not checked yetcites Casero and Marton, 2007
• Not checked yetcites Gerner and Meyskens, 2004

In the paper

“One possibility is that the inactivation of ASL and ASS1 allows cancer cells to accumulate ornithine, which is then utilized in the production of polyamines, a class of nitrogen-containing polycationic aliphatic carbon molecules.”

In the paper

“For instance, sirtuins, a class of deacetylases that catalyze the removal of acetyl marks from histone and non-histone proteins, utilize NAD+ as a cofactor, while FAD serves as a cofactor for a lysine-specific demethylase LSD1 (Imai et al., 2000; Shi et al., 2004).”

What the sources say

• Not checked yetcites Imai et al., 2000 source
• Not checked yetcites Shi et al., 2004 source

In the paper

“Reciprocally, proline oxidase (POX), which mediates proline degradation, is negatively controlled by c-myc via miR-23b, and is a p53 target as well (Donald et al., 2001; Liu et al., 2012).”

What the sources say

• Not checked yetcites Donald et al., 2001
• Not checked yetcites Liu et al., 2012

In the paper

“Among α-ketoglutarate-dependent dioxygenases are a TET family of DNA demethylases, Jumonji C family of histone demethylases, mRNA demethylases FTO and ALKBH5, and a family of prolyl hydroxylase (PHD) enzymes, which, among other processes, regulate HIF1α levels in response to oxygen availability and oxidative stress.”

In the paper

“Argininosuccinate, in turn, is produced by the enzyme argininosuccinate synthase (ASS1) from citrulline and aspartate.”

In the paper

“SAM is a product of the one-carbon metabolic pathway and is fueled by serine catabolism as described above.”

In the paper

“Tumors that exhibit SDH- and FH loss share a number of phenotypic features that are consistent with dioxygenase inhibition, among which is a characteristic global increase in DNA methylation (Killian et al., 2013; Letouze et al., 2013; Xiao et al., 2012), as well as elevated levels of HIF1α (Selak et al., 2005).”

What the sources say

• Not checked yetcites Killian et al., 2013 source
• Not checked yetcites Letouze et al., 2013 source
• Not checked yetcites Xiao et al., 2012 source

In the paper

“Proline can be produced either from glutamate or from arginine-derived ornithine via a common intermediate, pyrroline-5-carboxylate.”

In the paper

“Indeed, withdrawal and readdition of glucose, as well as activation of oncogenic signaling via introduction of an oncogenic KRAS mutant or a constitutively active form of Akt, increase total histone acetylation, which, in turn, promotes the enhanced and broader gene expression (Lee et al., 2014).”

What the sources say

• Not checked yetcites Lee et al., 2014 source

In the paper

“The de novo biosynthesis of arginine is an integral part of the urea cycle, where it is derived from argininosuccinate in a cleavage reaction catalyzed by argininosuccinate lyase (ASL).”

In the paper

“The deposition of acetyl marks on histones is associated with the increased accessibility of the genomic DNA for the assembly of transcriptional complexes, and has a rapid turnover rate.”

In the paper

“As discussed earlier, tumors are often faced with nutrient- and oxygen-poor surroundings and develop various nutrient-scavenging strategies to bypass these limitations.”

In the paper

“Furthermore, hypoxia impedes the ability of cells to carry out oxidative phosphorylation and other reactions that require oxygen and disrupts the redox balance, affecting cellular signaling and transcriptional programs.”

In the paper

“a gasotransmitter with complex and not yet fully defined functions in cellular physiology, among which are protection from oxidative stress, increased mitochondrial respiration, protection from apoptosis and facilitation of angiogenesis (Wu et al., 2015).”

What the sources say

• Not checked yetcites Wu et al., 2015

In the paper

“Oncogene-driven metabolic reprogramming allows cancer cells to maintain deregulated proliferation, withstand metabolic challenges that are associated with oxygen and nutrient limitations, maintain a dedifferentiated state through alterations in global patterns of gene expression, and corrupt the surrounding microenvironment into actively assisting tumor growth and dissemination.”

In the paper

“Increased extracellular acidification stimulates the proteolytic activity of matrix metalloproteinases (MMPs) and cathepsins, promoting the degradation of the extracellular matrix components and enhancing tumor invasion (Martinez-Zaguilan et al., 1996; Rothberg et al., 2013).”

What the sources say

• Not checked yetcites Martinez-Zaguilan et al., 1996
• Not checked yetcites Rothberg et al., 2013

In the paper

“Thus, cancer cells upregulate the uptake of cysteine via the transcriptional upregulation of the xCT transporter, as well as secondary to the increased rate of glutamine utilization by cells (Lo et al., 2008).”

What the sources say

• Not checked yetcites Lo et al., 2008

In the paper

“Thus, lactate promotes the stabilization of HIF1α and activates NF-κB and PI-3 kinase signaling in endothelial cells, as well as induces secretion of a pro-angiogenic factor VEGF from tumor-associated stromal cells (Constant et al., 2000; Schmid et al., 2007; Sonveaux et al., 2012; Vegran et al., 2011).”

What the sources say

• Not checked yetcites Constant et al., 2000 source
• Not checked yetcites Schmid et al., 2007
• Not checked yetcites Sonveaux et al., 2012

In the paper

“How cancer cells reprogram their microenvironment to assist tumor growth and dissemination is an area of intense investigation, but it is clear that such reprogramming encompasses multiple strategies, among which are secreted growth factors and alterations to the extracellular matrix and cell-cell interactions.”

In the paper

“In addition, a specific increase in the L enantiomer of 2-HG, which was shown to exert similar, but not identical, inhibitory effects on α-ketoglutarate-dependent dioxygenases was found in clear cell renal cell carcinoma, where it correlates with increased methylcytosine levels (Shim et al., 2014).”

What the sources say

• Not checked yetcites Shim et al., 2014 source

In the paper

“Increased choline uptake is observed in breast and prostate cancer; in fact, radioactive 18F- and 11C-choline is used in the clinic for PET-based tumor imaging (Krause et al., 2013; Kwee et al., 2007).”

What the sources say

• Not checked yetcites Krause et al., 2013
• Not checked yetcites Kwee et al., 2007

In the paper

“In various cellular settings, ectopic expression of a mutant IDH allele or treatment with exogenous D-2-HG is sufficient to induce DNA and histone hypermethylation and block cellular differentiation (Losman et al., 2013; Lu et al., 2012).”

What the sources say

• Not checked yetcites Losman et al., 2013 source
• Not checked yetcites Lu et al., 2012

In the paper

“Increased levels of lactate also stimulate hyaluronic acid production by fibroblasts, which may contribute to tumor invasiveness (Stern et al., 2002).”

What the sources say

• Not checked yetcites Stern et al., 2002

In the paper

“Specifically, numerous solid tumor types overexpress tryptophan-degrading dioxygenases indoleamine-2, 3-dioxygenase (IDO1) and tryptophan-2, 3-dioxygenase (TDO2), which catalyze the conversion of an essential amino acid, tryptophan, into its derivative, kynurenine (Munn and Mellor, 2007).”

What the sources say

• Not checked yetcites Munn and Mellor, 2007

In the paper

“In addition, lactate stimulates the polarization of resident macrophages to a so-called M2 state, which plays a role in immunosuppression and wound healing (Carmona-Fontaine et al., 2013; Colegio et al., 2014).”

What the sources say

• Not checked yetcites Carmona-Fontaine et al., 2013
• Not checked yetcites Colegio et al., 2014 source

In the paper

“Finally, kynurenine potentiates autocrine signaling through AhR on cancer cells themselves, promoting the degradation of the extracellular matrix and invasion (Opitz et al., 2011).”

What the sources say

• Not checked yetcites Opitz et al., 2011

In the paper

“While most of the studies to this point have been focused on alterations in the metabolism of glucose and glutamine, cancer cells utilize a great variety of other nutrients, among which are sulfur–containing amino acids cysteine and methionine, essential fatty acids, choline, trace metals, and vitamins.”

In the paper

“IDH mutations in AML are mutually exclusive with inactivating mutations in TET2 methylcytosine hydroxylases, further implicating mutant IDH as a bona fide driver of epigenetic remodeling (Figueroa et al., 2010).”

What the sources say

• Not checked yetcites Figueroa et al., 2010 source

In the paper

“In a manner that is dependent on AhR, kynurenine promotes regulatory T-cell phenotype, further contributing to the suppression of antitumor immune responses (Fallarino et al., 2006).”

What the sources say

• Not checked yetcites Fallarino et al., 2006

In the paper

“Micronutrients are utilized as cofactors for various enzymes and play complex and not yet fully defined roles in regulating cellular metabolic circuits, as well as signal transduction.”

In the paper

“Interestingly, copper was recently shown to be required for BRAFV600E-driven ERK activation in melanoma cells, and the effect of copper depletion could be rescued by the constitutive activation of ERK (Brady et al., 2014).”

What the sources say

• Not checked yetcites Brady et al., 2014

In the paper

“As many cancers are characterized by increased methylation of CpG islands, alterations in ascorbic acid import may thus affect their epigenetic state as well.”

In the paper

“For instance, ascorbic acid acts as a cofactor for the α-ketoglutarate-dependent dioxygenases.”