Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Cancer Metabolism: Fueling More than Just Growth

  • Lee, Namgyu (Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School) ;
  • Kim, Dohoon (Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School)
  • Received : 2016.12.16
  • Accepted : 2016.12.20
  • Published : 2016.12.31
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Abstract

The early landmark discoveries in cancer metabolism research have uncovered metabolic processes that support rapid proliferation, such as aerobic glycolysis (Warburg effect), glutaminolysis, and increased nucleotide biosynthesis. However, there are limitations to the effectiveness of specifically targeting the metabolic processes which support rapid proliferation. First, as other normal proliferative tissues also share similar metabolic features, they may also be affected by such treatments. Secondly, targeting proliferative metabolism may only target the highly proliferating "bulk tumor" cells and not the slowergrowing, clinically relevant cancer stem cell subpopulations which may be required for an effective cure. An emerging body of research indicates that altered metabolism plays key roles in supporting proliferation-independent functions of cancer such as cell survival within the ischemic and acidic tumor microenvironment, immune system evasion, and maintenance of the cancer stem cell state. As these aspects of cancer cell metabolism are critical for tumor maintenance yet are less likely to be relevant in normal cells, they represent attractive targets for cancer therapy.

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References

  1. Anastasiou, D., Poulogiannis, G., Asara, J.M., Boxer, M.B., Jiang, J.K., Shen, M., Bellinger, G., Sasaki, A.T., Locasale, J.W., Auld, D.S., et al. (2011). Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 334, 1278-1283. https://doi.org/10.1126/science.1211485
  2. Antonioli, L., Blandizzi, C., Pacher, P., and Hasko, G. (2013). Immunity, inflammation and cancer: a leading role for adenosine. Nat. Rev. Cancer 13, 842-857. https://doi.org/10.1038/nrc3613
  3. Barker, N. (2014). Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nat. Rev. Mol. Cell Biol. 15, 19-33.
  4. Bouma, M.G., Jeunhomme, T.M., Boyle, D.L., Dentener, M.A., Voitenok, N.N., van den Wildenberg, F. A., and Buurman, W.A. (1997). Adenosine inhibits neutrophil degranulation in activated human whole blood: involvement of adenosine A2 and A3 receptors. J. Immunol. 158, 5400-5408.
  5. Brand, A., Singer, K., Koehl, G. E., Kolitzus, M., Schoenhammer, G., Thiel, A., Matos, C., Bruss, C., Klobuch, S., Peter, K., et al. (2016). LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK cells. Cell Metab. 24, 657-671. https://doi.org/10.1016/j.cmet.2016.08.011
  6. Carmona-Fontaine, C., Bucci, V., Akkari, L., Deforet, M., Joyce, J.A., and Xavier, J.B. (2013). Emergence of spatial structure in the tumor microenvironment due to the Warburg effect. Proc. Natl. Acad. Sci. USA, 110, 19402-19407. https://doi.org/10.1073/pnas.1311939110
  7. Chaneton, B., Hillmann, P., Zheng, L., Martin, A. C., Maddocks, O. D., Chokkathukalam, A., Coyle, J.E., Jankevics, A., Holding, F.P., Vousden, K.H., et al. (2012). Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature 491, 458-462. https://doi.org/10.1038/nature11540
  8. Chen, K., Huang, Y.H., and Chen, J.L. (2013). Understanding and targeting cancer stem cells: therapeutic implications and challenges. Acta Pharmacol. Sin. 34, 732-740. https://doi.org/10.1038/aps.2013.27
  9. Chiche, J., Brahimi-Horn, M.C., and Pouyssegur, J. (2010). Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer. J. Cell Mol. Med. 14, 771-794. https://doi.org/10.1111/j.1582-4934.2009.00994.x
  10. Chowdhury, R., Yeoh, K.K., Tian, Y.M., Hillringhaus, L., Bagg, E.A., Rose, N.R., Leung, I.K., Li, X.S., Woon, E.C., Yang, M., et al. (2011). The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 12, 463-469. https://doi.org/10.1038/embor.2011.43
  11. Christofk, H.R., Vander Heiden, M.G., Harris, M.H., Ramanathan, A., Gerszten, R.E., Wei, R., Fleming, M.D., Schreiber, S.L., and Cantley, L.C. (2008). The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452, 230-233. https://doi.org/10.1038/nature06734
  12. Christofk, H.R., Vander Heiden, M.G., Wu, N., Asara, J.M., and Cantley, L.C. (2008). Pyruvate kinase M2 is a phosphotyrosinebinding protein. Nature 452, 181-186. https://doi.org/10.1038/nature06667
  13. Colegio, O.R., Chu, N.Q., Szabo, A.L., Chu, T., Rhebergen, A.M., Jairam, V., Cyrus, N., Brokowski, C.E., Eisenbarth, S.C., Phillips, G.M., et al. (2014). Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559-563. https://doi.org/10.1038/nature13490
  14. Condeelis, J., and Pollard, J.W. (2006). Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263-266. https://doi.org/10.1016/j.cell.2006.01.007
  15. de Medina, P., Paillasse, M.R., Segala, G., Voisin, M., Mhamdi, L., Dalenc, F., Lacroix-Triki, M., Filleron, T., Pont, F., Saati, T.A., et al. (2013). Dendrogenin A arises from cholesterol and histamine metabolism and shows cell differentiation and anti-tumour properties. Nat. Commun. 4, 1840. https://doi.org/10.1038/ncomms2835
  16. Di Francesco, A.M., Toesca, A., Cenciarelli, C., Giordano, A., Gasbarrini, A., and Puglisi, M.A. (2016). Metabolic modification in gastrointestinal cancer stem cells: characteristics and therapeutic approaches. J. Cell Physiol. 231, 2081-2087. https://doi.org/10.1002/jcp.25318
  17. Eppell, B.A., Newell, A.M., and Brown, E.J. (1989). Adenosine receptors are expressed during differentiation of monocytes to macrophages in vitro. Implications for regulation of phagocytosis. J. Immunol. 143, 4141-4145.
  18. Fallarino, F., Grohmann, U., Vacca, C., Bianchi, R., Orabona, C., Spreca, A., Fioretti, M.C., and Puccetti, P. (2002). T cell apoptosis by tryptophan catabolism. Cell Death Differ. 9, 1069-1077. https://doi.org/10.1038/sj.cdd.4401073
  19. Fallarino, F., Grohmann, U., Vacca, C., Orabona, C., Spreca, A., Fioretti, M.C., and Puccetti, P. (2003). T cell apoptosis by kynurenines. Adv. Exp. Med. Biol. 527, 183-190. https://doi.org/10.1007/978-1-4615-0135-0_21
  20. Fan, J., Ye, J., Kamphorst, J.J., Shlomi, T., Thompson, C.B., and Rabinowitz, J.D. (2014). Quantitative flux analysis reveals folatedependent NADPH production. Nature 510, 298-302. https://doi.org/10.1038/nature13236
  21. Farber, S., and Diamond, L.K. (1948). Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl. J. Med. 238, 787-793. https://doi.org/10.1056/NEJM194806032382301
  22. Farkona, S., Diamandis, E.P., and Blasutig, I.M. (2016). Cancer immunotherapy: the beginning of the end of cancer? BMC Med. 14, 73. https://doi.org/10.1186/s12916-016-0623-5
  23. Fischer, K., Hoffmann, P., Voelkl, S., Meidenbauer, N., Ammer, J., Edinger, M., Gottfried, E., Schwarz, S., Rothe, G., Hoves, S., et al. (2007). Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109, 3812-3819. https://doi.org/10.1182/blood-2006-07-035972
  24. Fox, C.J., Hammerman, P.S., and Thompson, C.B. (2005). Fuel feeds function: energy metabolism and the T-cell response. Nat. Rev. Immunol. 5, 844-852. https://doi.org/10.1038/nri1710
  25. Gajewski, T.F., Schreiber, H., and Fu, Y.X. (2013). Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 14, 1014-1022. https://doi.org/10.1038/ni.2703
  26. Galon, J., Costes, A., Sanchez-Cabo, F., Kirilovsky, A., Mlecnik, B., Lagorce-Pages, C., Tosolini, M., Camus, M., Berger, A., Wind, P., et al. (2006). Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960-1964. https://doi.org/10.1126/science.1129139
  27. Giannoni, E., Bianchini, F., Calorini, L., and Chiarugi, P. (2011). Cancer associated fibroblasts exploit reactive oxygen species through a proinflammatory signature leading to epithelial mesenchymal transition and stemness. Antioxid. Redox. Signal. 14, 2361-2371. https://doi.org/10.1089/ars.2010.3727
  28. Gimenez-Roqueplo, A.P., Favier, J., Rustin, P., Rieubland, C., Crespin, M., Nau, V., Khau Van Kien, P., Corvol, P., Plouin, P.F., Jeunemaitre, X., et al. (2003). Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res. 63, 5615-5621.
  29. Goetze, K., Walenta, S., Ksiazkiewicz, M., Kunz-Schughart, L.A., and Mueller-Klieser, W. (2011). Lactate enhances motility of tumor cells and inhibits monocyte migration and cytokine release. Int. J. Oncol. 39, 453-463.
  30. Gottfried, E., Kunz-Schughart, L. A., Ebner, S., Mueller-Klieser, W., Hoves, S., Andreesen, R., Mackensen, A., and Kreutz, M. (2006). Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood 107, 2013-2021. https://doi.org/10.1182/blood-2005-05-1795
  31. Hanahan, D., and Weinberg, R.A. (2011). Hallmarks of cancer: the next generation. Cell 144, 646-674. https://doi.org/10.1016/j.cell.2011.02.013
  32. Hasko, G., Szabo, C., Nemeth, Z.H., Kvetan, V., Pastores, S.M., and Vizi, E.S. (1996). Adenosine receptor agonists differentially regulate IL-10, TNF-alpha, and nitric oxide production in RAW 264.7 macrophages and in endotoxemic mice. J. Immunol. 157, 4634-4640.
  33. Hasko, G., Linden, J., Cronstein, B., and Pacher, P. (2008). Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat. Rev. Drug Discov. 7, 759-770. https://doi.org/10.1038/nrd2638
  34. Hausler, S.F., Montalban del Barrio, I., Strohschein, J., Chandran, P.A., Engel, J.B., Honig, A., Ossadnik, M., Horn, E., Fischer, B., Krockenberger, M., et al. (2011). Ectonucleotidases CD39 and CD73 on OvCA cells are potent adenosine-generating enzymes responsible for adenosine receptor 2A-dependent suppression of T cell function and NK cell cytotoxicity. Cancer Immunol. Immunother. 60, 1405-1418. https://doi.org/10.1007/s00262-011-1040-4
  35. Ho, P.C., Bihuniak, J.D., Macintyre, A.N., Staron, M., Liu, X., Amezquita, R., Tsui, Y.C., Cui, G., Micevic, G., Perales, J.C., et al. (2015). Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162, 1217-1228. https://doi.org/10.1016/j.cell.2015.08.012
  36. Hsu, P.P., and Sabatini, D.M. (2008). Cancer cell metabolism: Warburg and beyond. Cell 134, 703-707. https://doi.org/10.1016/j.cell.2008.08.021
  37. Intlekofer, A.M., Dematteo, R.G., Venneti, S., Finley, L.W., Lu, C., Judkins, A.R., Rustenburg, A.S., Grinaway, P.B., Chodera, J.D., Cross, J.R., et al. (2015). Hypoxia induces production of L-2- hydroxyglutarate. Cell Metab. 22, 304-311. https://doi.org/10.1016/j.cmet.2015.06.023
  38. Isaacs, J.S., Jung, Y.J., Mole, D.R., Lee, S., Torres-Cabala, C., Chung, Y.L., Merino, M., Trepel, J., Zbar, B., Toro, J., et al. (2005). HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 8, 143-153. https://doi.org/10.1016/j.ccr.2005.06.017
  39. Jain, M., Nilsson, R., Sharma, S., Madhusudhan, N., Kitami, T., Souza, A.L., Kafri, R., Kirschner, M.W., Clish, C.B., and Mootha, V.K. (2012). Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336, 1040-1044. https://doi.org/10.1126/science.1218595
  40. Jang, H., Yang, J., Lee, E., and Cheong, J.H. (2015). Metabolism in embryonic and cancer stemness. Arch. Pharm. Res. 38, 381-388. https://doi.org/10.1007/s12272-015-0558-y
  41. Kalluri, R., and Weinberg, R.A. (2009). The basics of epithelialmesenchymal transition. J. Clin. Invest. 119, 1420-1428. https://doi.org/10.1172/JCI39104
  42. Kim, J.W., Tchernyshyov, I., Semenza, G.L., and Dang, C.V. (2006). HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3, 177-185. https://doi.org/10.1016/j.cmet.2006.02.002
  43. Kim, D., Fiske, B.P., Birsoy, K., Freinkman, E., Kami, K., Possemato, R.L., Chudnovsky, Y., Pacold, M.E., Chen, W.W., Cantor, J.R., et al. (2015a). SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance. Nature 520, 363-367. https://doi.org/10.1038/nature14363
  44. Kim, H., Jang, H., Kim, T.W., Kang, B.H., Lee, S.E., Jeon, Y.K., Chung, D.H., Choi, J., Shin, J., Cho, E.J., et al. (2015b). Core pluripotency factors directly regulate metabolism in embryonic stem cell to maintain pluripotency. Stem Cells 33, 2699-2711. https://doi.org/10.1002/stem.2073
  45. Klimova, T., and Chandel, N.S. (2008). Mitochondrial complex III regulates hypoxic activation of HIF. Cell Death Differ. 15, 660-666. https://doi.org/10.1038/sj.cdd.4402307
  46. Koivunen, P., Lee, S., Duncan, C.G., Lopez, G., Lu, G., Ramkissoon, S., Losman, J.A., Joensuu, P., Bergmann, U., Gross, S., et al. (2012). Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483, 484-488. https://doi.org/10.1038/nature10898
  47. Letouze, E., Martinelli, C., Loriot, C., Burnichon, N., Abermil, N., Ottolenghi, C., Janin, M., Menara, M., Nguyen, A.T., Benit, P., et al. (2013). SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23, 739-752. https://doi.org/10.1016/j.ccr.2013.04.018
  48. Losman, J.A., Looper, R.E., Koivunen, P., Lee, S., Schneider, R.K., McMahon, C., Cowley, G.S., Root, D.E., Ebert, B.L., and Kaelin, W.G. Jr. (2013). (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 339, 1621-1625. https://doi.org/10.1126/science.1231677
  49. Lu, C., Ward, P.S., Kapoor, G.S., Rohle, D., Turcan, S., Abdel- Wahab, O., Edwards, C.R., Khanin, R., Figueroa, M.E., Melnick, A., et al. (2012). IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474-478. https://doi.org/10.1038/nature10860
  50. Luo, W., Hu, H., Chang, R., Zhong, J., Knabel, M., O'Meally, R., Cole, R.N., Pandey, A., and Semenza, G.L. (2011). Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145, 732-744. https://doi.org/10.1016/j.cell.2011.03.054
  51. McGuire, J.J. (2003). Anticancer antifolates: current status and future directions. Curr. Pharm. Des. 9, 2593-2613. https://doi.org/10.2174/1381612033453712
  52. Mimeault, M., and Batra, S.K. (2013). Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells. J. Cell Mol. Med. 17, 30-54. https://doi.org/10.1111/jcmm.12004
  53. Moore, N., and Lyle, S. (2011). Quiescent, slow-cycling stem cell populations in cancer: a review of the evidence and discussion of significance. J. Oncol. 2011. pii: 396076
  54. Munn, D.H., and Mellor, A.L. (2007). Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J. Clin. Invest. 117, 1147-1154. https://doi.org/10.1172/JCI31178
  55. Neumann, H.P., Pawlu, C., Peczkowska, M., Bausch, B., McWhinney, S.R., Muresan, M., Buchta, M., Franke, G., Klisch, J., Bley, T.A., et al. (2004). Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 292, 943-951. https://doi.org/10.1001/jama.292.8.943
  56. Papandreou, I., Cairns, R.A., Fontana, L., Lim, A.L., and Denko, N.C. (2006). HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 3, 187-197. https://doi.org/10.1016/j.cmet.2006.01.012
  57. Parks, S.K., Chiche, J., and Pouyssegur, J. (2011). pH control mechanisms of tumor survival and growth. J. Cell Physiol. 226, 299-308. https://doi.org/10.1002/jcp.22400
  58. Pearce, E.L., and Pearce, E.J. (2013). Metabolic pathways in immune cell activation and quiescence. Immunity 38, 633-643. https://doi.org/10.1016/j.immuni.2013.04.005
  59. Pilotte, L., Larrieu, P., Stroobant, V., Colau, D., Dolusic, E., Frederick, R., De Plaen, E., Uyttenhove, C., Wouters, J., Masereel, B., et al. (2012). Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc. Natl. Acad. Sci. USA 109, 2497-2502. https://doi.org/10.1073/pnas.1113873109
  60. Possemato, R., Marks, K.M., Shaul, Y.D., Pacold, M.E., Kim, D., Birsoy, K., Sethumadhavan, S., Woo, H.K., Jang, H.G., Jha, A.K., et al. (2011). Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476, 346-350. https://doi.org/10.1038/nature10350
  61. Rohle, D., Popovici-Muller, J., Palaskas, N., Turcan, S., Grommes, C., Campos, C., Tsoi, J., Clark, O., Oldrini, B., Komisopoulou, E., et al. (2013). An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340, 626-630. https://doi.org/10.1126/science.1236062
  62. Ryzhov, S., Novitskiy, S.V., Goldstein, A.E., Biktasova, A., Blackburn, M. R., Biaggioni, I., Dikov, M.M., and Feoktistov, I. (2011). Adenosinergic regulation of the expansion and immunosuppressive activity of CD11b+Gr1+ cells. J. Immunol. 187, 6120-6129. https://doi.org/10.4049/jimmunol.1101225
  63. Sancho, P., Barneda, D., and Heeschen, C. (2016). Hallmarks of cancer stem cell metabolism. Br. J. Cancer 114, 1305-1312. https://doi.org/10.1038/bjc.2016.152
  64. Sciacovelli, M., Goncalves, E., Johnson, T.I., Zecchini, V.R., da Costa, A.S., Gaude, E., Drubbel, A.V., Theobald, S.J., Abbo, S.R., Tran, M.G., et al. (2016). Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature 537, 544-547. https://doi.org/10.1038/nature19353
  65. Selak, M.A., Armour, S.M., MacKenzie, E.D., Boulahbel, H., Watson, D.G., Mansfield, K.D., Pan, Y., Simon, M.C., Thompson, C.B., and Gottlieb E. (2005). Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7, 77-85. https://doi.org/10.1016/j.ccr.2004.11.022
  66. Semenza, G.L. (2012). Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol. Sci. 33, 207-214. https://doi.org/10.1016/j.tips.2012.01.005
  67. Shaul, Y.D., Freinkman, E., Comb, W.C., Cantor, J.R., Tam, W.L., Thiru, P., Kim D2, Kanarek, N., Pacold, M.E., Chen, W.W., et al. (2014). Dihydropyrimidine accumulation is required for the epithelial-mesenchymal transition. Cell 158, 1094-1109. https://doi.org/10.1016/j.cell.2014.07.032
  68. Shaul, Y.D., Yuan, B., Thiru, P., Nutter-Upham, A., McCallum, S., Lanzkron, C., Bell, G.W., and Sabatini, D.M. (2016). MERAV: a tool for comparing gene expression across human tissues and cell types. Nucleic Acids Res. 44, D560-566. https://doi.org/10.1093/nar/gkv1337
  69. Siemann, D.W. (2011). The unique characteristics of tumor vasculature and preclinical evidence for its selective disruption by tumor-vascular disrupting agents. Cancer Treat. Rev. 37, 63-74. https://doi.org/10.1016/j.ctrv.2010.05.001
  70. Stagg, J., and Smyth, M. J. (2010). Extracellular adenosine triphosphate and adenosine in cancer. Oncogene 29, 5346-5358. https://doi.org/10.1038/onc.2010.292
  71. Takahashi, T., Otsuguro, K., Ohta, T., and Ito, S. (2010). Adenosine and inosine release during hypoxia in the isolated spinal cord of neonatal rats. Br. J. Pharmacol. 161, 1806-1816. https://doi.org/10.1111/j.1476-5381.2010.01002.x
  72. Terunuma, A., Putluri, N., Mishra, P., Mathe, E.A., Dorsey, T.H., Yi, M., Wallace, T.A., Issaq, H.J., Zhou, M., Killian, J.K., et al. (2014). MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis. J. Clin. Invest, 124, 398-412. https://doi.org/10.1172/JCI71180
  73. Vander Heiden, M.G., Cantley, L.C., and Thompson, C.B. (2009). Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029-1033. https://doi.org/10.1126/science.1160809
  74. Vaupel, P., and Mayer, A. (2016). Hypoxia-driven adenosine accumulation: a crucial microenvironmental factor promoting tumor progression. Adv. Exp. Med. Biol. 876, 177-183. https://doi.org/10.1007/978-1-4939-3023-4_22
  75. Vesely, M.D., Kershaw, M.H., Schreiber, R.D., and Smyth, M.J. (2011). Natural innate and adaptive immunity to cancer. Annu. Rev. Immunol. 29, 235-271. https://doi.org/10.1146/annurev-immunol-031210-101324
  76. Vinogradov, S., and Wei, X. (2012). Cancer stem cells and drug resistance: the potential of nanomedicine. Nanomedicine 7, 597-615. https://doi.org/10.2217/nnm.12.22
  77. Visentin, M., Zhao, R., and Goldman, I.D. (2012). The antifolates. Hematol. Oncol. Clin. North Am. 26, 629-648, ix. https://doi.org/10.1016/j.hoc.2012.02.002
  78. Wang, F., Travins, J., DeLaBarre, B., Penard-Lacronique, V., Schalm, S., Hansen, E., Straley, K., Kernytsky, A., Liu, W., Gliser, C., et al. (2013). Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340, 622-626. https://doi.org/10.1126/science.1234769
  79. Warburg, O. (1956). On the origin of cancer cells. Science 123, 309-314. https://doi.org/10.1126/science.123.3191.309
  80. Ward, P.S., Patel, J., Wise, D.R., Abdel-Wahab, O., Bennett, B.D., Coller, H.A., Fantin, V.R., Hedvat, C.V., Perl, A.E., Rabinowitz, J.D., et al. (2010). The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17, 225-234. https://doi.org/10.1016/j.ccr.2010.01.020
  81. Webb, B.A., Chimenti, M., Jacobson, M.P., and Barber, D.L. (2011). Dysregulated pH: a perfect storm for cancer progression. Nat. Rev. Cancer 11, 671-677. https://doi.org/10.1038/nrc3110
  82. Xiao, M., Yang, H., Xu, W., Ma, S., Lin, H., Zhu, H., Liu, L., Liu, Y., Yang, C., Xu, Y., et al. (2012). Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 26, 1326-1338. https://doi.org/10.1101/gad.191056.112
  83. Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.H., Ito, S., Yang, C., Wang, P., Xiao, M.T., et al. (2011). Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutaratedependent dioxygenases. Cancer Cell 19, 17-30. https://doi.org/10.1016/j.ccr.2010.12.014
  84. Yang, M., Soga, T., and Pollard, P.J. (2013). Oncometabolites: linking altered metabolism with cancer. J. Clin. Invest. 123, 3652-3658. https://doi.org/10.1172/JCI67228
  85. Yang, M., and Vousden, K.H. (2016). Serine and one-carbon metabolism in cancer. Nat. Rev. Cancer 16, 650-662. https://doi.org/10.1038/nrc.2016.81
  86. Ye, J., Fan, J., Venneti, S., Wan, Y.W., Pawel, B.R., Zhang, J., Finley, L.W., Lu, C., Lindsten, T., Cross, J.R., et al. (2014). Serine catabolism regulates mitochondrial redox control during hypoxia. Cancer Discov. 4, 1406-1417. https://doi.org/10.1158/2159-8290.CD-14-0250
  87. Zhang, W.C., Shyh-Chang, N., Yang, H., Rai, A., Umashankar, S., Ma, S., Soh, B.S., Sun, L.L., Tai, B.C., Nga, M.E., et al. (2012). Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell 148, 259-272. https://doi.org/10.1016/j.cell.2011.11.050

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