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How close is the bench to the bedside? Metabolic profiling in cancer research.

Van QN, Veenstra TD - Genome Med (2009)

Bottom Line: Metabolic profiling using mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR) is integral to the rapidly expanding field of metabolomics, which is making progress in toxicology, plant science and various diseases, including cancer.In the area of oncology and metabolic phenotyping, researchers have probed the known changes in malignant cellular pathways using new experimental techniques to gain more insights, and others are exploiting these same cellular pathways for therapeutic drug targets and for novel cancer biomarkers, with the ultimate goal of translation to the clinic.Here, we discuss the challenges and opportunities in metabolic phenotyping for discovering novel cancer biomarkers, and we assess the clinical applicability of MS and NMR.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Proteomics and Analytical Technologies, Advanced Technology Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD 21702, USA.

ABSTRACT
Metabolic profiling using mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR) is integral to the rapidly expanding field of metabolomics, which is making progress in toxicology, plant science and various diseases, including cancer. In the area of oncology and metabolic phenotyping, researchers have probed the known changes in malignant cellular pathways using new experimental techniques to gain more insights, and others are exploiting these same cellular pathways for therapeutic drug targets and for novel cancer biomarkers, with the ultimate goal of translation to the clinic. Here, we discuss the challenges and opportunities in metabolic phenotyping for discovering novel cancer biomarkers, and we assess the clinical applicability of MS and NMR.

No MeSH data available.


Related in: MedlinePlus

Metabolic reprogramming in tumor cells. The alteration of bioenergetic pathways in tumor cells is evident from their increased glucose uptake (a) through glycolysis (b), the intermediate metabolites of which are also shuttled into biosynthetic pathways (synthesis of nucleic acids from glucose 6-phosphate through the pentose phosphate pathway (c), amino acids from glycerate 3-phosphate (not shown) and lipogenesis from pyruvate (d)) that are necessary for cell growth and proliferation. In tumor cells, pyruvate in the mitochondria is shuttled into a truncated tricarboxylic acid cycle where it is converted to acetyl-CoA by pyruvate dehydrogenase and combined with oxaloacetate for export into the cytosol as citrate for the synthesis of isoprenoids, cholesterol and fatty acids. Open up and down arrows indicate upregulation and downregulation of enzymes, respectively. Enzymes upregulated by activation of HIF-1 are in red. Abbreviations: ACL, adenosine triphosphate citrate lyase; ADP, adenosine diphosphate; ATP, adenosine triphosphate; CA9 and CA12, carbonic anhydrases 9 and 12; CPT1A, carnitine palmitoyltransferase 1A; FASN, fatty acid synthase; G6P, glucose 6-phosphate; GLUT1,3,4, glucose transporter 1, 3 and 4; GSH, glutathione; HIF-1, hypoxia-inducible factor 1; HK1,2, hexokinase1 and 2; LAT1, L-type amino acid transporter 1; LDH-A, lactate dehydrogenase A; MCT4, monocarboxylate transporter 4; M2-PK, pyruvate kinase isoform M2; NAD+, nicotinamide adenine dinucleotide oxidized; NADH, nicotinamide adenine dinucleotide reduced; NADPH, nicotinamide adenine dinucleotide phosphate; NHE1, Na+/H+ exchanger 1; OAA, oxaloacetate; OXPHOS, oxidative phosphorylation; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase 1; PFK2, phosphofructokinase 2; PGM, phosphoglycerate mutase; PI3K, phosphatidylinositol 3-kinase; PPP, pentose phosphate pathway; TLK1, transketolase 1; VDAC, voltage-dependent anion channel. Reproduced with permission from [2].
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Figure 1: Metabolic reprogramming in tumor cells. The alteration of bioenergetic pathways in tumor cells is evident from their increased glucose uptake (a) through glycolysis (b), the intermediate metabolites of which are also shuttled into biosynthetic pathways (synthesis of nucleic acids from glucose 6-phosphate through the pentose phosphate pathway (c), amino acids from glycerate 3-phosphate (not shown) and lipogenesis from pyruvate (d)) that are necessary for cell growth and proliferation. In tumor cells, pyruvate in the mitochondria is shuttled into a truncated tricarboxylic acid cycle where it is converted to acetyl-CoA by pyruvate dehydrogenase and combined with oxaloacetate for export into the cytosol as citrate for the synthesis of isoprenoids, cholesterol and fatty acids. Open up and down arrows indicate upregulation and downregulation of enzymes, respectively. Enzymes upregulated by activation of HIF-1 are in red. Abbreviations: ACL, adenosine triphosphate citrate lyase; ADP, adenosine diphosphate; ATP, adenosine triphosphate; CA9 and CA12, carbonic anhydrases 9 and 12; CPT1A, carnitine palmitoyltransferase 1A; FASN, fatty acid synthase; G6P, glucose 6-phosphate; GLUT1,3,4, glucose transporter 1, 3 and 4; GSH, glutathione; HIF-1, hypoxia-inducible factor 1; HK1,2, hexokinase1 and 2; LAT1, L-type amino acid transporter 1; LDH-A, lactate dehydrogenase A; MCT4, monocarboxylate transporter 4; M2-PK, pyruvate kinase isoform M2; NAD+, nicotinamide adenine dinucleotide oxidized; NADH, nicotinamide adenine dinucleotide reduced; NADPH, nicotinamide adenine dinucleotide phosphate; NHE1, Na+/H+ exchanger 1; OAA, oxaloacetate; OXPHOS, oxidative phosphorylation; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase 1; PFK2, phosphofructokinase 2; PGM, phosphoglycerate mutase; PI3K, phosphatidylinositol 3-kinase; PPP, pentose phosphate pathway; TLK1, transketolase 1; VDAC, voltage-dependent anion channel. Reproduced with permission from [2].

Mentions: The reduction of the burden of disease on society depends on early screening and detection to enable timely therapeutic regimens when these therapies are likely to be most effective. The ideal biological marker(s) for cancer risk assessment and early detection must have high sensitivity and specificity, be found in a biosample obtained using minimally invasive procedures, and be analyzed using a high-throughput, cost-effective assay. In lieu of early detection biomarkers, prognostic biomarkers can empower physicians in the selection of the most effective therapy for treating an active tumor. The importance of studying the cellular metabolome for the discovery of biomarkers has been shown throughout studies conducted over the last few decades. Tumor cells are adept at evading the host's immune surveillance, apoptosis and anti-growth checkpoints to sustain angiogenesis and limitless replication [2]. Some of these characteristics can be traced back to the reprogramming of cellular bioenergetic pathways. The key pathways that behave differently between tumor and normal cells include the glycolysis and pentose phosphate pathways, nucleotide and protein biosynthesis, lipid and phospholipid turnover, the citric acid cycle and redox stress pathways (Figure 1) [2,3]. Essentially all pathways needed for cellular growth and proliferation are affected, and many of these have been targeted for drug research and development [2,4]. Several metabolites are commonly found to be elevated in tumors, including lactate, choline-containing compounds, nucleosides, myoinositol and lipids [5]. As investigators continue to drill down from gene expression to metabolite end products, new hypotheses emerge concerning common metabolites. For example, recent evidence shows that lactate may act as a regulator of glycolysis and mitochondrial physiology, and not simply be a waste product of glycolysis [6].


How close is the bench to the bedside? Metabolic profiling in cancer research.

Van QN, Veenstra TD - Genome Med (2009)

Metabolic reprogramming in tumor cells. The alteration of bioenergetic pathways in tumor cells is evident from their increased glucose uptake (a) through glycolysis (b), the intermediate metabolites of which are also shuttled into biosynthetic pathways (synthesis of nucleic acids from glucose 6-phosphate through the pentose phosphate pathway (c), amino acids from glycerate 3-phosphate (not shown) and lipogenesis from pyruvate (d)) that are necessary for cell growth and proliferation. In tumor cells, pyruvate in the mitochondria is shuttled into a truncated tricarboxylic acid cycle where it is converted to acetyl-CoA by pyruvate dehydrogenase and combined with oxaloacetate for export into the cytosol as citrate for the synthesis of isoprenoids, cholesterol and fatty acids. Open up and down arrows indicate upregulation and downregulation of enzymes, respectively. Enzymes upregulated by activation of HIF-1 are in red. Abbreviations: ACL, adenosine triphosphate citrate lyase; ADP, adenosine diphosphate; ATP, adenosine triphosphate; CA9 and CA12, carbonic anhydrases 9 and 12; CPT1A, carnitine palmitoyltransferase 1A; FASN, fatty acid synthase; G6P, glucose 6-phosphate; GLUT1,3,4, glucose transporter 1, 3 and 4; GSH, glutathione; HIF-1, hypoxia-inducible factor 1; HK1,2, hexokinase1 and 2; LAT1, L-type amino acid transporter 1; LDH-A, lactate dehydrogenase A; MCT4, monocarboxylate transporter 4; M2-PK, pyruvate kinase isoform M2; NAD+, nicotinamide adenine dinucleotide oxidized; NADH, nicotinamide adenine dinucleotide reduced; NADPH, nicotinamide adenine dinucleotide phosphate; NHE1, Na+/H+ exchanger 1; OAA, oxaloacetate; OXPHOS, oxidative phosphorylation; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase 1; PFK2, phosphofructokinase 2; PGM, phosphoglycerate mutase; PI3K, phosphatidylinositol 3-kinase; PPP, pentose phosphate pathway; TLK1, transketolase 1; VDAC, voltage-dependent anion channel. Reproduced with permission from [2].
© Copyright Policy
Related In: Results  -  Collection

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Figure 1: Metabolic reprogramming in tumor cells. The alteration of bioenergetic pathways in tumor cells is evident from their increased glucose uptake (a) through glycolysis (b), the intermediate metabolites of which are also shuttled into biosynthetic pathways (synthesis of nucleic acids from glucose 6-phosphate through the pentose phosphate pathway (c), amino acids from glycerate 3-phosphate (not shown) and lipogenesis from pyruvate (d)) that are necessary for cell growth and proliferation. In tumor cells, pyruvate in the mitochondria is shuttled into a truncated tricarboxylic acid cycle where it is converted to acetyl-CoA by pyruvate dehydrogenase and combined with oxaloacetate for export into the cytosol as citrate for the synthesis of isoprenoids, cholesterol and fatty acids. Open up and down arrows indicate upregulation and downregulation of enzymes, respectively. Enzymes upregulated by activation of HIF-1 are in red. Abbreviations: ACL, adenosine triphosphate citrate lyase; ADP, adenosine diphosphate; ATP, adenosine triphosphate; CA9 and CA12, carbonic anhydrases 9 and 12; CPT1A, carnitine palmitoyltransferase 1A; FASN, fatty acid synthase; G6P, glucose 6-phosphate; GLUT1,3,4, glucose transporter 1, 3 and 4; GSH, glutathione; HIF-1, hypoxia-inducible factor 1; HK1,2, hexokinase1 and 2; LAT1, L-type amino acid transporter 1; LDH-A, lactate dehydrogenase A; MCT4, monocarboxylate transporter 4; M2-PK, pyruvate kinase isoform M2; NAD+, nicotinamide adenine dinucleotide oxidized; NADH, nicotinamide adenine dinucleotide reduced; NADPH, nicotinamide adenine dinucleotide phosphate; NHE1, Na+/H+ exchanger 1; OAA, oxaloacetate; OXPHOS, oxidative phosphorylation; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase 1; PFK2, phosphofructokinase 2; PGM, phosphoglycerate mutase; PI3K, phosphatidylinositol 3-kinase; PPP, pentose phosphate pathway; TLK1, transketolase 1; VDAC, voltage-dependent anion channel. Reproduced with permission from [2].
Mentions: The reduction of the burden of disease on society depends on early screening and detection to enable timely therapeutic regimens when these therapies are likely to be most effective. The ideal biological marker(s) for cancer risk assessment and early detection must have high sensitivity and specificity, be found in a biosample obtained using minimally invasive procedures, and be analyzed using a high-throughput, cost-effective assay. In lieu of early detection biomarkers, prognostic biomarkers can empower physicians in the selection of the most effective therapy for treating an active tumor. The importance of studying the cellular metabolome for the discovery of biomarkers has been shown throughout studies conducted over the last few decades. Tumor cells are adept at evading the host's immune surveillance, apoptosis and anti-growth checkpoints to sustain angiogenesis and limitless replication [2]. Some of these characteristics can be traced back to the reprogramming of cellular bioenergetic pathways. The key pathways that behave differently between tumor and normal cells include the glycolysis and pentose phosphate pathways, nucleotide and protein biosynthesis, lipid and phospholipid turnover, the citric acid cycle and redox stress pathways (Figure 1) [2,3]. Essentially all pathways needed for cellular growth and proliferation are affected, and many of these have been targeted for drug research and development [2,4]. Several metabolites are commonly found to be elevated in tumors, including lactate, choline-containing compounds, nucleosides, myoinositol and lipids [5]. As investigators continue to drill down from gene expression to metabolite end products, new hypotheses emerge concerning common metabolites. For example, recent evidence shows that lactate may act as a regulator of glycolysis and mitochondrial physiology, and not simply be a waste product of glycolysis [6].

Bottom Line: Metabolic profiling using mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR) is integral to the rapidly expanding field of metabolomics, which is making progress in toxicology, plant science and various diseases, including cancer.In the area of oncology and metabolic phenotyping, researchers have probed the known changes in malignant cellular pathways using new experimental techniques to gain more insights, and others are exploiting these same cellular pathways for therapeutic drug targets and for novel cancer biomarkers, with the ultimate goal of translation to the clinic.Here, we discuss the challenges and opportunities in metabolic phenotyping for discovering novel cancer biomarkers, and we assess the clinical applicability of MS and NMR.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Proteomics and Analytical Technologies, Advanced Technology Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD 21702, USA.

ABSTRACT
Metabolic profiling using mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR) is integral to the rapidly expanding field of metabolomics, which is making progress in toxicology, plant science and various diseases, including cancer. In the area of oncology and metabolic phenotyping, researchers have probed the known changes in malignant cellular pathways using new experimental techniques to gain more insights, and others are exploiting these same cellular pathways for therapeutic drug targets and for novel cancer biomarkers, with the ultimate goal of translation to the clinic. Here, we discuss the challenges and opportunities in metabolic phenotyping for discovering novel cancer biomarkers, and we assess the clinical applicability of MS and NMR.

No MeSH data available.


Related in: MedlinePlus