Famine versus feast: Understanding the metabolism of tumors in vivo

Trends in Biochemical Sciences

Volumn 40, Issue 3, 2015, Pages 130-140

  Mayers, Jared R ^a   Vander Heiden, Matthew G ^a,b,c  

^a MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^b DANA FARBER CANCER INSTITUTE   (United States)

^c BROAD INSTITUTE OF MIT AND HARVARD   (United States)

Author keywords

Cancer metabolism; Cell proliferation; Nutrient availability; Tumor metabolism

Indexed keywords

ACETIC ACID; ACETIC ACID C 11; AMINO ACID; FLUORODEOXYGLUCOSE F 18; GLUCOSE; GLUCOSE C 13; GLUTAMATE F 18; GLUTAMINE; RADIOISOTOPE; UNCLASSIFIED DRUG;

AMINO ACID METABOLISM; CANCER CELL; CANCER CELL CULTURE; CATABOLISM; CELL HETEROGENEITY; CELL METABOLISM; CELL PROLIFERATION; CITRIC ACID CYCLE; CULTURE MEDIUM; GLUCOSE METABOLISM; GLYCOLYSIS; HUMAN; IN VITRO STUDY; IN VIVO STUDY; MACROMOLECULE; METABOLISM; NEOPLASM; NONHUMAN; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; NUTRIENT UPTAKE; POSITRON EMISSION TOMOGRAPHY; REVIEW; ANIMAL; ENERGY METABOLISM; FOOD; PHYSIOLOGY; STARVATION;

ANIMALS; ENERGY METABOLISM; FOOD; GLUCOSE; GLUTAMINE; HUMANS; NEOPLASMS; STARVATION;

EID: 84923186422     PISSN: 09680004     EISSN: 13624326     Source Type: Journal    
DOI: 10.1016/j.tibs.2015.01.004     Document Type: Review

References (117)

1. Gaglio D., et al. Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Mol. Syst. Biol. 2011, 7:523.
2. Vizan P. K-ras codon-specific mutations produce distinctive metabolic phenotypes in human fibroblasts. Cancer Res. 2005, 65:5512-5515.
3. Wise D.R., et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc. Natl. Acad. Sci. U.S.A. 2008, 105:18782-18787.
4. Gao P., et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 2009, 458:762-765.
5. Wang R., et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 2011, 35:871-882.
6. Shim H., et al. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc. Natl. Acad. Sci. U.S.A. 1997, 94:6658-6663.
7. Schwartzenberg-Bar-Yoseph F., et al. The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res. 2004, 64:2627-2633.
8. Bensaad K., et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 2006, 126:107-120.
9. Maddocks O., Vousden K.H. Metabolic regulation by p53. J. Mol. Med. 2011, 89:237-245.
10. Cairns R.A., et al. Regulation of cancer cell metabolism. Nat. Rev. Cancer 2011, 11:85-95.
11. Lemons J.M.S., et al. Quiescent fibroblasts exhibit high metabolic activity. PLoS Biol. 2010, 8:e1000514.
12. Khairallah M. Profiling substrate fluxes in the isolated working mouse heart using 13C-labeled substrates: focusing on the origin and fate of pyruvate and citrate carbons. Am. J. Physiol. Heart Circ. Physiol. 2003, 286:H1461-H1470.
13. Metallo C.M., Vander Heiden M.G. Understanding metabolic regulation and its influence on cell physiology. Mol. Cell 2013, 49:388-398.
14. Drake K.J., et al. Amino acids as metabolic substrates during cardiac ischemia. Exp. Biol. Med. 2012, 237:1369-1378.
15. Owen O.E., et al. Brain metabolism during fasting. J. Clin. Invest. 1967, 46:1589-1595.
16. Israelsen W.J., et al. PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 2013, 155:397-409.
17. Warburg O., Posener K. Ueber den Stoffwechsel der Carcinomzelle. Die Naturwissenschaften 1924, 12:1131-1137.
18. Lunt S.Y., Vander Heiden M.G. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu. Rev. Cell Dev. Biol. 2011, 27:441-464.
19. Boros L.G., et al. Transforming growth factor beta2 promotes glucose carbon incorporation into nucleic acid ribose through the nonoxidative pentose cycle in lung epithelial carcinoma cells. Cancer Res. 2000, 60:1183-1185.
20. Ying H., et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 2012, 149:656-670.
21. Lunt S.Y., et al. Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation. Mol. Cell. 2014, Published online December 3, 2014. http://dx.doi.org/j.molcel.2014.10.027.
22. Fuster M.M., Esko J.D. The sweet and sour of cancer: glycans as novel therapeutic targets. Nat. Rev. Cancer 2005, 5:526-542.
23. Fang M., et al. The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg effect, and proliferation in the PTEN pathway. Cell 2010, 143:711-724.
24. Possemato R., et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 2011, 476:346-350.
25. Locasale J.W., et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat. Genet. 2011, 43:869-874.
26. Jain M., et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 2012, 336:1040-1044.
27. Stein W.H., Moore S. The free amino acids of human blood plasma. J. Biol. Chem. 1954, 211:915.
28. Eagle H., et al. The growth response of mammalian cells in tissue culture to L-glutamine and L-glutamic acid. J. Biol. Chem. 1956, 218:607-616.
29. Deberardinis R.J., et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc. Natl. Acad. Sci. U.S.A. 2007, 104:19345-19350.
30. Son J., et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 2013, 496:101-105.
31. Labuschagne C.F., et al. Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. Cell Rep. 2014, 7:1248-1258.
32. Maddocks O.D.K., et al. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 2012, 493:542-546.
33. Lewis C.A., et al. Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells. Mol. Cell 2014, 55:253-263.
34. Ye J., et al. Serine catabolism regulates mitochondrial redox control during hypoxia. Cancer Discov. 2014, 4:1406-1417.
35. Dolfi S.C., et al. The metabolic demands of cancer cells are coupled to their size and protein synthesis rates. Cancer Metab. 2013, 1:20.
36. Tönjes M., et al. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat. Med. 2013, 19:901-908.
37. Yan H., et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 2009, 360:765-773.
38. Prabhu A., et al. Cysteine catabolism: a novel metabolic pathway contributing to glioblastoma growth. Cancer Res. 2014, 74:787-796.
39. Chung W.J., et al. Inhibition of cystine uptake disrupts the growth of primary brain tumors. J. Neurosci. 2005, 25:7101-7110.
40. Ogunrinu T.A., Sontheimer H. Hypoxia increases the dependence of glioma cells on glutathione. J. Biol. Chem. 2010, 285:37716-37724.
41. Zhang J., et al. Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol. Cell 2014, 56:205-218.
42. Liu W., et al. Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC. Proc. Natl. Acad. Sci. U.S.A. 2012, 109:8983-8988.
43. Bar-Sagi D., Feramisco J.R. Induction of membrane ruffling and fluid-phase pinocytosis in quiescent fibroblasts by ras proteins. Science 1986, 233:1061-1068.
44. Commisso C., et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 2013, 497:633-637.
45. Kamphorst, J.J. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Research (in press).
46. Kamphorst J.J., et al. Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc. Natl. Acad. Sci. U.S.A. 2013, 110:8882-8887.
47. Metallo C.M., et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 2011, 481:380-384.
48. Mullen A.R., et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 2011, 481:385-388.
49. Wise D.R., et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Natl. Acad. Sci. U.S.A. 2011, 108:19611-19616.
50. Fendt S-M., et al. Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells. Nat. Commun. 2013, 4:2236.
51. Kamphorst J.J., et al. Quantitative analysis of acetyl-CoA production in hypoxic cancer cells reveals substantial contribution from acetate. Cancer Metab. 2014, 2:23.
52. Mashimo T., et al. Acetate Is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 2014, 159:1603-1614.
53. Schug Z.T. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 2015, 27:57-71.
54. Comerford S.A., et al. Acetate dependence of tumors. Cell 2014, 159:1591-1602.
55. Birsoy K., et al. Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature 2014, 508:108-112.
56. Puchowicz M.A., et al. Zonation of acetate labeling across the liver: implications for studies of lipogenesis by MIDA. Am. J. Physiol. 1999, 277:E1022-E1027.
57. Hirayama A., et al. Quantitative metabolome profiling of colon and stomach cancer microenvironment by capillary electrophoresis time-of-flight mass spectrometry. Cancer Res. 2009, 69:4918-4925.
58. Tatum J.L., et al. Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. Int. J. Radiat. Biol. 2006, 82:699-757.
59. Helmlinger G., et al. Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat. Med. 1997, 3:177-182.
60. Vaupel P., et al. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res. 1989, 49:6449-6465.
61. Hu J., et al. Heterogeneity of tumor-induced gene expression changes in the human metabolic network. Nat. Biotechnol. 2013, 31:522-529.
62. Yuneva M.O., et al. The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. Cell Metab. 2012, 15:157-170.
63. Everhart J., Wright D. Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis. JAMA 1995, 273:1605-1609.
64. Wang F., et al. The relationship between diabetes and pancreatic cancer. Mol. Cancer 2003, 2:1-5.
65. Khasawneh J., et al. Inflammation and mitochondrial fatty acid β-oxidation link obesity to early tumor promotion. Proc. Natl. Acad. Sci. U.S.A. 2009, 106:3354.
66. Zyromski N.J., et al. Obesity potentiates the growth and dissemination of pancreatic cancer. Surgery 2009, 146:258-263.
67. Pannala R., et al. New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer. Lancet Oncol. 2009, 10:88-95.
68. Pannala R., et al. Temporal association of changes in fasting blood glucose and body mass index with diagnosis of pancreatic cancer. Am. J. Gastroenterol. 2009, 104:2318-2325.
69. Dewys W.D., et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am. J. Med. 1980, 69:491-497.
70. Wigmore S.J., et al. Changes in nutritional status associated with unresectable pancreatic cancer. Br. J. Cancer 1997, 75:106-109.
71. Kir S., et al. Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature 2014, 513:100-104.
72. Shukla S.K., et al. Metabolic reprogramming induced by ketone bodies diminishes pancreatic cancer cachexia. Cancer Metab. 2014, 2:18.
73. Mayers J.R., et al. Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat. Med. 2014, 20:1193-1198.
74. Patel A.P., et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 2014, 344:1396-1401.
75. Sonveaux P., et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J. Clin. Invest. 2008, 118:3930-3942.
76. Guillaumond F., et al. Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma. Proc. Natl. Acad. Sci. U.S.A. 2013, 110:3919-3924.
77. Pavlides S., et al. The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 2009, 8:3984-4001.
78. Pavlides S., et al. Warburg meets autophagy: cancer-associated fibroblasts accelerate tumor growth and metastasis via oxidative stress, mitophagy, and aerobic glycolysis. Antioxid. Redox Signal. 2012, 16:1264-1284.
79. Chaudhri V.K., et al. Metabolic alterations in lung cancer-associated fibroblasts correlated with increased glycolytic metabolism of the tumor. Mol. Cancer Res. 2013, 11:579-592.
80. Nieman K.M., et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat. Med. 2011, 17:1498-1503.
81. Zhang W., et al. Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia. Nat. Cell Biol. 2012, 14:276-286.
82. McDonnell L.A., Heeren R. Imaging mass spectrometry. Mass Spectrom. Rev. 2007, 26:606-643.
83. Steinhauser M.L., et al. Multi-isotope imaging mass spectrometry quantifies stem cell division and metabolism. Nature 2012, 481:516-519.
84. Hawkins R.A., Phelps M.E. PET in clinical oncology. Cancer Metastasis Rev. 1988, 7:119-142.
85. 18F-FDG PET and PET/CT in the evaluation of cancer treatment response. J. Nucl. Med. 2009, 50:88-99.
86. 18F]fluoropropyl)-l-glutamate for omaging xC-transporter using positron emission tomography in patients with non-small cell lung or breast cancer. Cancer Res. 2012, 18:5427-5437.
87. 18F-(2S,4R)4-fluoroglutamine. J. Nucl. Med. 2011, 52:1947-1955.
88. 11C-acetate PET imaging in hepatocellular carcinoma and other liver masses. J. Nucl. Med. 2003, 44:213-221.
89. Sakurai Y., Klein S. Metabolic alteration in patients with cancer: nutritional implications. Surg. Today 1998, 28:247-257.
90. Holroyde C.P., et al. Altered glucose metabolism in metastatic carcinoma. Cancer Res. 1975, 35:3710-3714.
91. Shaw J.H., Wolfe R.R. Glucose and urea kinetics in patients with early and advanced gastrointestinal cancer: the response to glucose infusion, parenteral feeding, and surgical resection. Surgery 1987, 101:181-191.
92. Inculet R.I., et al. Altered leucine metabolism in noncachectic sarcoma patients. Cancer Res. 1987, 47:4746-4749.
93. Shaw J.H., Wolfe R.R. Fatty acid and glycerol kinetics in septic patients and in patients with gastrointestinal cancer. The response to glucose infusion and parenteral feeding. Ann. Surg. 1987, 205:368-376.
94. 13C-labeled glucose. Nat. Med. 2014, 20:93-97.
95. 13C MR for molecular omaging of prostate cancer. J. Nucl. Med. 2014, 55:1567-1572.
96. Marin-Valencia I., et al. Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo. Cell Metab. 2012, 15:827-837.
97. 13C]glucose in human brain tumors in vivo. NMR Biomed. 2012, 25:1234-1244.
98. Yang L., et al. Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer. Mol. Syst. Biol. 2014, 10:728.
99. Physician's Guide to the Laboratory Diagnosis of Metabolic Diseases 2003, Springer. 2nd edn. N. Blau (Ed.).
100. Standard Values in Blood 1952, W.B. Saunders. E.C. Albritton (Ed.).
101. McMenamy R.H., et al. Unbound amino acid concentrations in human blood plasmas. J. Clin. Invest. 1957, 36:1672-1679.
102. Newgard C.B., et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 2009, 9:311-326.
103. Pitkänen H.T., et al. Serum amino acid concentrations in aging men and women. Amino Acids 2003, 24:413-421.
104. Wuu J.A., et al. Amino acid concentrations in serum and aqueous humor from subjects with extreme myopia or senile cataract. Clin. Chem. 1988, 34:1610-1613.
105. Eagle H. The specific amino acid requirements of a human carcinoma cell (strain HeLa) in tissue culture. J. Exp. Med. 1955, 102:37-48.
106. Eagle H. The specific amino acid requirements of a mammalian cell (strain L) in tissue culture. J. Biol. Chem. 1955, 214:839-852.
107. Eagle H. Amino acid metabolism in mammalian cell cultures. Science 1959, 130:432-437.
108. Vogt M., Dulbecco R. Virus-cell interaction with a tumor-producing virus. Proc. Natl. Acad. Sci. U.S.A. 1960, 46:365-370.
109. Moore G.E. Culture of normal human leukocytes. JAMA 1967, 199:519.
110. Tollinger C.D., et al. Measurement of acetate in human blood by gas chromatography: effects of sample preparation, feeding, and various diseases. Clin. Chem. 1979, 25:1787-1790.
111. Hoffmann G.F., et al. Physiology and pathophysiology of organic acids in cerebrospinal fluid. J. Inherit. Metab. Dis. 1993, 16:648-669.
112. Rangarajan A., Weinberg R.A. Opinion: comparative biology of mouse versus human cells: modelling human cancer in mice. Nat. Rev. Cancer 2003, 3:952-959.
113. Ames B.N., et al. Oxidants, antioxidants, and the degenerative diseases of aging. Proc. Natl. Acad. Sci. U.S.A. 1993, 90:7915-7922.
114. Chandrasekera P.C., Pippin J.J. Of rodents and men: species-specific glucose regulation and type 2 diabetes research. ALTEX 2014, 31:157-176.
115. Harper A., et al. Branched-chain amino acid metabolism. Annu. Rev. Nutr. 1984, 4:409-454.
116. Harper A.E. Some concluding comments on emerging aspects of amino acid metabolism. J. Nutr. 1994, 124:1529S-1532S.
117. Kim, D. et al. SHMT2 drives glioma cell survival in the tumor microenvironment but imposes a dependence on glycine clearance. Nature (in press).