Metabolic control of cancer cell stemness: Lessons from iPS cells

Cell Cycle

Volumn 14, Issue 24, 2015, Pages 3801-3811

  Menendez, Javier A ^a,b  

^a CATALAN INSTITUTE OF ONCOLOGY   (Spain)

^b GIRONA BIOMEDICAL RESEARCH INSTITUTE IDIBGI   (Spain)

Author keywords

Cancer stem cells; Epigenetic landscapes; Metabolism; Reprogramming; Stemness; Waddington

Indexed keywords

CANCER CELL; CANCER STEM CELL; CANCER TISSUE; CELL FATE; CELL METABOLISM; DNA TRANSCRIPTION; DRIVER; EPIGENETICS; GENETIC TRANSCRIPTION; HUMAN; HUMAN EXPERIMENT; KINETICS; METABOLIC REGULATION; MODULATION; NUCLEAR REPROGRAMMING; PLURIPOTENT STEM CELL; TRANSCRIPTION REGULATION; ANIMAL; GENETIC EPIGENESIS; GENETICS; INDUCED PLURIPOTENT STEM CELL; METABOLISM; PHYSIOLOGY;

ANIMALS; CELLULAR REPROGRAMMING; EPIGENESIS, GENETIC; HUMANS; INDUCED PLURIPOTENT STEM CELLS; NEOPLASTIC STEM CELLS;

EID: 84964054269     PISSN: 15384101     EISSN: 15514005     Source Type: Journal    
DOI: 10.1080/15384101.2015.1022697     Document Type: Article

References (146)

1. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126:663-76; PMID:16904174; http://dx.doi.org/10.1016/jxell.2006.07.024
2. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med 2006; 355:1253-61; PMID:16990388; http://dx.doi.org/10.1056/NEJMra061808
3. Dalerba P, Cho RW, Clarke MF. Cancer stem cells: models and concepts. Annu Rev Med 2007; 58: 26784; PMID:17002552; http://dx.doi.org/10.1146/annurev.med.58.062105.204854
4. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3:730-7; PMID:9212098; http://dx.doi.org/10.1038/nm0797-730
5. Nguyen LV, Vanner R, Dirks P, Eaves CJ. Cancer stem cells: an evolving concept. Nat Rev Cancer 2012; 12:133-43; PMID:22237392
6. Cozzio A, Passegue E, Ayton PM, Karsunky H, Cleary ML, Weissman IL. Similar ML L-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev 2003; 17:3029-35; PMID:14701873; http://dx.doi.org/10.1101/gad.1143403
7. Yoo MH, Hatfield DL. The cancer stem cell theory: is it correct? Mol Cells 2008;26:514-6;PMID:18711315
8. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med 2009; 15:1010-2; PMID:19734877; http://dx.doi.org/10.1038/nm0909-1010
9. Scheel C, Weinberg RA. Cancer stem cells and epithe-lial-mesenchymal transition: concepts and molecular links. Semin Cancer Biol 2012; 22:396-403; PMID:22554795; http://dx.doi.org/10.1016/j.semcancer.2012.04.001
10. Marjanovic ND, Weinberg RA, Chaffer CL. Cell plasticity and heterogeneity in cancer. Clin Chem 2013; 59:168-79; PMID:23220226; http://dx.doi.org/10.1373/clinchem.2012.184655
11. Tomasson MH. Cancer stem cells: a guide for skeptics. J Cell Biochem 2009; 106:745-9; PMID:19184979; http://dx.doi.org/10.1002/jcb.22050
12. Lee AS, Tang C, Rao MS, Weissman IL, Wu JC. Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies. Nat Med 2013; 19:998-1004; PMID:23921754; http://dx.doi.org/10.1038/nm.3267
13. Suva ML, Riggi N, Bernstein BE. Epigenetic reprog-ramming in cancer. Science 2013; 339:1567-70; PMID:23539597; http://dx.doi.org/10.1126/science.1230184
14. Ben-David U, Benvenisty N. The tumorigenicity of human embryonic and induced pluripotent stem cells. Nat Rev Cancer 2011; 11:268-77; PMID:21390058; http://dx.doi.org/10.1038/nrc3034
15. Riggs JW, Barrilleaux BL, Varlakhanova N, Bush KM, Chan V, Knoepfler PS. Induced pluripotency and oncogenic transformation are related processes. Stem Cells Dev 2013; 22:37-50; PMID:22998387; http://dx.doi.org/10.1089/scd.2012.0375
16. Menendez JA, Joven J, Cufi S, Corominas-Faja B, Oliveras-Ferraros C, Cuyas E, Martin-Castillo B, Lopez-Bonet E, Alarcon T, Vazquez-Martin A. The Warburg effect version 2.0: metabolic reprogramming of cancer stem cells. Cell Cycle 2013; 12:1166-79; PMID:23549172;http://dx.doi.org/10.4161/cc.24479
17. Corominas-Faja B, Cufi S, Oliveras-Ferraros C, Cuyas E, Loopez-Bonet E, Lupu R, Alarcoon T, Vellon L, Igle-sias JM, Leis O, et al. Nuclear reprogramming of luminal-like breast cancer cells generates Sox2-overex-pressing cancer stem-like cellular states harboring tran-scriptional activation of the mTOR pathway. Cell Cycle 2013; 12:3109-24; PMID:23974095; http://dx.doi.org/10.4161/cc.26173
18. Vazquez-Martin A, Cufi S, Lopez-Bonet E, Corominas-Faja B, Cuyas E, Vellon L, Iglesias JM, Leis O, Martin AG, Menendez JA. Reprogramming of non-genomic estrogen signaling by the stemness factor SOX2 enhances the tumor-initiating capacity of breast cancer cells. Cell Cycle 2013; 12:3471-7; PMID:24107627; http://dx.doi.org/10.4161/cc.26692
19. Menendez JA, Alarcon T, Corominas-Faja B, Cuyas E, Loopez-Bonet E, Martin AG, Vellon L. Xenopatients 2.0: reprogramming the epigenetic landscapes of patient-derived cancer genomes. Cell Cycle 2014; 13:358-70; PMID:24406535; http://dx.doi.org/10.4161/cc.27770
20. Friedmann-Morvinski D, Verma IM. Dedifferentia-tion and reprogramming: origins of cancer stem cells. EMBO Rep 2014; 15:244-53; PMID:24531722; http://dx.doi.org/10.1002/embr.201338254
21. Goding CR, Pei D, Lu X. Cancer: pathological nuclear reprogramming? Nat Rev Cancer 2014; 14:568-73; PMID:25030952; http://dx.doi.org/10.1038/nrc3781
22. Ohnishi K, Semi K, Yamamoto T, Shimizu M, Tanaka A, Mitsunaga K, Okita K, Osafune K, Arioka Y, Maeda T, et al. Premature termination of reprog-ramming in vivo leads to cancer development through altered epigenetic regulation. Cell 2014; 156:663-77; PMID:24529372; http://dx.doi.org/10.1016/j.cell.2014.01.005
23. Knoepfler PS. Deconstructing stem cell tumorigenicity: a roadmap to safe regenerative medicine. Stem Cells 2009; 27:1050-1056; PMID:19415771; http://dx.doi.org/10.1002/stem.37
24. Tung PY, Knoepfler PS. Epigenetic mechanisms of tumorigenicity manifesting in stem cells. Oncogene 2014; PMID:AMBIGUOUS
25. Prigione A, Adjaye J. Modulation of mitochondrial biogenesis and bioenergetic metabolism upon in vitro and in vivo differentiation of human ES and iPS cells. Int J Dev Biol 2010; 54:1729-41; PMID:21305470; http://dx.doi.org/10.1387/ijdb.103198ap
26. Menendez JA, Vellon L, Oliveras-Ferraros C, Cufo S, Vazquez-Martin A. mTOR-regulated senescence and autophagy during reprogramming of somatic cells to pluripotency: a roadmap from energy metabolism to stem cell renewal and aging. Cell Cycle 2011; 10:3658-77; PMID:22052357; http://dx.doi.org/10.4161/cc.10.21.18128
27. Chen CT, Hsu SH, Wei YH. Mitochondrial bioener-getic function and metabolic plasticity in stem cell differentiation and cellular reprogramming. Biochim Biophys Acta 2012; 1820:571-6; PMID:21983491; http://dx.doi.org/10.1016/j.bbagen.2011.09.013
28. Folmes CD, Nelson TJ, Terzic A. Energy metabolism in nuclear reprogramming. Biomark Med 2011; 5:715-29; PMID:22103608; http://dx.doi.org/10.2217/bmm.11.87
29. Zhang J, Nuebel E, Daley GQ, Koehler CM, Teitell MA. Metabolic regulation in pluripotent stem cells during reprogramming and self-renewal. Cell Stem Cell 2012; 11:589-95; PMID:23122286; http://dx.doi.org/10.1016/j.stem.2012.10.005
30. Xu X, Duan S, Yi F, Ocampo A, Liu GH, Izpisua Bel-monte JC. Mitochondrial regulation in pluripotent stem cells. Cell Metab 2013; 18:325-32; PMID:23850316; http://dx.doi.org/10.1016/j.cmet.2013.06.005
31. Shyh-Chang N, Daley GQ, Cantley LC. Stem cell metabolism in tissue development and aging. Development 2013; 140:2535-47; PMID:23715547; http://dx.doi.org/10.1242/dev.091777
32. Ito K, Suda T. Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol 2014; 15:243-56; PMID:24651542; http://dx.doi.org/10.1038/nrm3772
33. Prigione A, Fauler B, Lurz R, Lehrach H, Adjaye J. The senescence-related mitochondrial/oxidative stress pathway is repressed in human induced pluripotent stem cells. Stem Cells 2010; 28:721-33; PMID:20201066; http://dx.doi.org/10.1002/stem.404
34. Prigione A, Adjaye J. Modulation of mitochondrial biogenesis and bioenergetic metabolism upon in vitro and in vivo differentiation of human ES and iPS cells. Int J Dev Biol 2010; 54:1729-41; PMID:21305470; http://dx.doi.org/10.1387/ijdb.103198ap
35. Prigione A, Lichtner B, Kuhl H, Struys EA, Wamelink M, Lehrach H, Ralser M, Timmermann B, Adjaye J. Human induced pluripotent stem cells harbor homo-plasmic and heteroplasmic mitochondrial DNA mutations while maintaining human embryonic stem cell-like metabolic reprogramming. Stem Cells 2011; 29:1338-48; PMID:21732474
36. Folmes CD, Nelson TJ, Martinez-Fernandez A, Arrell DK, Lindor JZ, Dzeja PP, Ikeda Y, Perez-Terzic C, Terzic A. Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metab 2011; 14:264-71; PMID:21803296; http://dx.doi.org/10.1016/j.cmet.2011.06.011
37. Varum S, Rodrigues AS, Moura MB, Momcilovic O, Easley CA 4th, Ramalho-Santos J, Van Houten B, Schatten G. Energy metabolism in human pluripotent stem cells and their differentiated counterparts. PLoS One 2011; 6:e20914; PMID:21698063; http://dx.doi.org/10.1371/journal.pone.0020914
38. Zhang J, Khvorostov I, Hong JS, Oktay Y, Vergnes L, Nuebel E, Wahjudi PN, Setoguchi K, Wang G, Do A, et al. UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells. EMBO J 2011; 30:4860-73; PMID:22085932; http://dx.doi.org/10.1038/emboj.2011.401
39. Shyh-Chang N, Zheng Y, Locasale JW, Cantley LC. Human pluripotent stem cells decouple respiration from energy production. EMBO J 2011; 30:4851-2; PMID:22166995; http://dx.doi.org/10.1038/emboj.2011.436
40. Folmes CD, Nelson TJ, Dzeja PP, Terzic A. Energy metabolism plasticity enables stemness programs. Ann N Y Acad Sci 2012; 1254:82-9; PMID:22548573; http://dx.doi.org/10.1111/j.1749-6632.2012.06487.x
41. Folmes CD, Dzeja PP, Nelson TJ, Terzic A. Metabolic plasticity in stem cell homeostasis and differentiation. Cell Stem Cell 2012; 11:596-606; PMID:23122287; http://dx.doi.org/10.1016/j.stem.2012.10.002
42. Panopoulos AD, Yanes O, Ruiz S, Kida YS, Diep D, Tautenhahn R, Herreroas A, Batchelder EM, Plongth-ongkum N, Lutz M, et al. The metabolome of induced pluripotent stem cells reveals metabolic changes occurring in somatic cell reprogramming. Cell Res 2012; 22:168-77; PMID:22064701; http://dx.doi.org/10.1038/cr.2011.177
43. Folmes CD, Arrell DK, Zlatkovic-Lindor J, Martinez-Fernandez A, Perez-Terzic C, Nelson TJ, Terzic A. Metabolome and metaboproteome remodeling in nuclear reprogramming. Cell Cycle 2013; 12:235-565; PMID:23839047; http://dx.doi.org/10.4161/cc.25509
44. Son MJ, Jeong BR, Kwon Y, Cho YS. Interference with the mitochondrial bioenergetics fuels reprogram-ming to pluripotency via facilitation of the glycolytic transition. Int JBiochem Cell Biol 2013; 45:2512-18; PMID:23939289; http://dx.doi.org/10.1016/j.biocel.2013.07.023
45. Liu W, Long Q, Chen K, Li S, Xiang G, Chen S, Liu X, Li Y, Yang L, Dong D, et al. Mitochondrial metabolism transition cooperates with nuclear reprogram-ming during induced pluripotent stem cell generation. Biochem Biophys Res Commun 2013; 431:767-71; PMID:23333381; http://dx.doi.org/10.1016/j.bbrc.2012.12.148
46. Prigione A, Rohwer N, Hoffmann S, Mlody B, Drews K, Bukowiecki R, Bliimlein K, Wanker EE, Ralser M, Cramer T, et al. HIF1a modulates cell fate reprogram-ming through early glycolytic shift and upregulation of PDK1-3 and PKM2. Stem Cells 2014; 32:364-76; PMID:24123565; http://dx.doi.org/10.1002/stem.1552
47. Bukowiecki R, Adjaye J, Prigione A. Mitochondrial function in pluripotent stem cells and cellular reprog-ramming. Gerontology 2014; 60:174-82; PMID:24281332; http://dx.doi.org/10.1159/000355050
48. Zhu S, Li W, Zhou H, Wei W, Ambasudhan R, Lin T, KimJ,ZhangK,DingS. Reprogrammingofhumanpri-mary somatic cells by OCT4 and chemical compounds. Cell Stem Cell 2010; 7:651-5; PMID:21112560; http://dx.doi.org/10.1016/j.stem.2010.11.015
49. Zhu H, Shyh-Chang N, Segre AV, Shinoda G, Shah SP, Einhorn WS, Takeuchi A, Engreitz JM, Hagan JP, Kha-ras MG, et al. The Lin28/let-7 axis regulates glucose metabolism. Cell 2011; 147:81-94; PMID:21962509; http://dx.doi.org/10.1016/j.cell.2011.08.033
50. Folmes CD, Martinez-Fernandez A, Faustino RS, Yamada S, Perez-Terzic C, Nelson TJ, Terzic A. Nuclear reprogramming with c-Myc potentiates glyco-lytic capacity of derived induced pluripotent stem cells. J Cardiovasc Transl Res 2013; 6:10-21; PMID:23247633; http://dx.doi.org/10.1007/s12265-012-9431-2
51. Vazquez-Martin A, Corominas-Faja B, Cufi S, Vellon L, Oliveras-Ferraros C, Menendez OJ, Joven J, Lupu R, Menendez JA. The mitochondrial H(C)-ATP syn-thase and the lipogenic switch: new core components of metabolic reprogramming in induced pluripotent stem (iPS) cells. Cell Cycle 2013; 12:207-18; PMID:23287468; http://dx.doi.org/10.4161/cc.23352
52. Soanchez-Aragoo M, Chamorro M, Cuezva JM. Selection ofcancercellswithrepressedmitochondriatriggerscolon cancer progression. Carcinogenesis 2010; 31:567-76; PMID:20080835; http://dx.doi.org/10.1093/carcin/bgq012
53. Soanchez-Cenizo L, Formentini L, Aldea M, Ortega AD, Garcoa-Huerta P, Soanchez-Aragoo M, Cuezva JM. Up-regulation of the ATPase inhibitory factor 1 (IF1) of the mitochondrial H+-ATP synthase in human tumors mediates the metabolic shift of cancer cells to a Warburg phenotype. J Biol Chem 2010; 285:2530-2813; PMID:20538613; http://dx.doi.org/10.1074/jbc.M110.146480
54. Willers IM, Cuezva JM. Post-transcriptional regulation of the mitochondrial H(C)-ATP synthase: a key regulator of the metabolic phenotype in cancer. Bio chim Biophys Acta 2011; 1807:543-51; PMID:21035425; http://dx.doi.org/10.1016/j.bbabio.2010.10.016
55. Aldea M, Clofent J, Nunez de Arenas C, Chamorro M, Velasco M, Berrendero JR, Navarro C, Cuezva JM. Reverse phase protein microarrays quantify and validate the bioenergetic signature as biomarker in colorectal cancer. Cancer Lett 2011; 311:210-8; PMID:21880415; http://dx.doi.org/10.1016/j.canlet.2011.07.022
56. Formentini L, Soanchez-Aragoo M, Soanchez-Cenizo L, Cuezva JM. The mitochondrial ATPase inhibitory factor 1 triggers a ROS-mediated retrograde prosurvival and proliferative response. Mol Cell 2012; 45:731-42; PMID:22342343; http://dx.doi.org/10.1016/j.molcel.2012.01.008
57. Soanchez-Aragoo M, Formentini L, Garcoa-Bermoudez J, Cuezva JM. IF1 reprograms energy metabolism and signals the oncogenic phenotype in cancer. Cell Cycle 2012; 11:2963-4; PMID:22871729; http://dx.doi.org/10.4161/cc.21387
58. Soanchez-Aragoo M, Formentini L, Cuezva JM. Mitochondria-mediated energy adaption in cancer: the H (C)-ATP synthase-geared switch of metabolism in human tumors. Antioxid Redox Signal 2013; 19:28598; PMID:22901241; http://dx.doi.org/10.1089/ars.2012.4883
59. Soanchez-Aragoo M, Formentini L, Martonez-Reyes I, Garcoa-Bermudez J, Santacatterina F, Soanchez-Cenizo L, Willers IM, Aldea M, Noajera L, Juarroanz A, et al. Expression, regulation and clinical relevance of the ATPase inhibitory factor 1 in human cancers. Onco- genesis 2013; 2:e46; PMID:23608753; http://dx.doi.org/10.1038/oncsis.2013.9
60. Soanchez-Aragoo M, Garcoa-Bermoudez J, Martonez-Reyes I, Santacatterina F, Cuezva JM. Degradation of IF1 controls energy metabolism during osteogenic differentiation of stem cells. EMBO Rep 2013; 14:63844; PMID:23722655; http://dx.doi.org/10.1038/embor.2013.72
61. Dong C, Yuan T, Wu Y, Wang Y, Fan TW, Miriyala S, Lin Y, Yao J, Shi J, Kang T, et al. Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer. Cancer Cell 2013: 23:316-31; PMID:23453623; http://dx.doi.org/10.1016/j.ccr.2013.01.022
62. Schieber MS, Chandel NS. ROS links glucose metabolism to breast cancer stem cell and EMT phenotype. Cancer Cell 2013; 23:265-7; PMID:23518342; http://dx.doi.org/10.1016/j.ccr.2013.02.021
63. Liu PP, Liao J, Tang ZJ, Wu WJ, Yang J, Zeng ZL, Hu Y, Wang P, Ju HQ, Xu RH, Huang P. Metabolic regulation of cancer cell side population by glucose through activation of the Akt pathway. Cell Death Differ 2014; 21:124-135; PMID:24096870; http://dx.doi.org/10.1038/cdd.2013.131
64. Ciavardelli D, Rossi C, Barcaroli D, Volpe S, Con-salvo A, Zucchelli M, De Cola A, Scavo E, Carollo R, D'Agostino D, et al. Breast cancer stem cells rely on fermentative glycolysis and are sensitive to 2-deoxyglu-cose treatment. Cell Death Dis 2014; 5:e1336; PMID:25032859; http://dx.doi.org/10.1038/cddis.2014.285
65. Perales-Clemente E, Folmes CD, Terzic A. Metabolic regulation of redox status in stem cells. Antioxid Redox Signal 2014; 21(11):1648-59; PMID:24949895; http://dx.doi.org/10.1089/ars.2014.6000
66. Saretzki G, Walter T, Atkinson S, Passos JF, Bareth B, Keith WN, Stewart R, Hoare S, Stojkovic M, Armstrong L,et al. Down regulation of multiple stressdefensemech-anisms during differentiation of human embryonic stem cells. Stem Cells 2008; 26:455-64; PMID:18055443; http://dx.doi.org/10.1634/stemcells.2007-0628
67. Armstrong L, Tilgner K, Saretzki G, Atkinson SP, Stojkovic M, Moreno R, Przyborski S, Lako M. Human induced pluripotent stem cell lines show stress defense mechanisms and mitochondrial regulation similar to those of human embryonic stem cells. Stem Cells 2010; 28:661-73; PMID:20073085; http://dx.doi.org/10.1002/stem.307
68. Yanes O, Clark J, Wong DM, Patti GJ, Soanchez-Ruiz A, BentonHP,TraugerSA,DespontsC,DingS,SiuzdakG. Metabolic oxidation regulates embryonic stem cell differentiation. Nat Chem Biol 2010; 6:411-7; PMID:20436487; http://dx.doi.org/10.1038/nchembio.364
69. Wang J, Alexander P, Wu L, Hammer R, Cleaver O, McKnight SL. Dependence of mouse embryonic stem cells on threonine catabolism. Science 2009; 325:4359; PMID:19589965; http://dx.doi.org/10.1126/science.1173288
70. Locasale JW, Cantley LC. Metabolic flux and the regulation of mammalian cell growth. Cell Metab 2011; 14:443-51; PMID:21982705; http://dx.doi.org/10.1016/j.cmet.2011.07.014
71. Son MJ, Son MY, Seol B, Kim MJ, Yoo CH, Han MK, Cho YS. Nicotinamide overcomes pluripotency deficits and reprogramming barriers. Stem Cells 2013; 31:1121-35; PMID:23526681; http://dx.doi.org/10.1002/stem.1368
72. Kobayashi CI, Suda T. Regulation of reactive oxygen species in stem cells and cancer stem cells. J Cell Physiol 2012; 227:421-30; PMID:21448925; http://dx.doi.org/10.1002/jcp.22764
73. Shi X, Zhang Y, Zheng J, Pan J. Reactive oxygen species in cancer stem cells. Antioxid Redox Signal 2012; 16:1215-28; PMID:22316005; http://dx.doi.org/10.1089/ars.2012.4529
74. Nagano O, Okazaki S, Saya H. Redox regulation in stem-like cancer cells by CD44 variant isoforms. Oncogene 2013; 32:5191-8; PMID:23334333; http://dx.doi.org/10.1038/onc.2012.638
75. Watson J. Oxidants, antioxidants and the current incurability of metastatic cancers. Open Biol 2013; 3:120-144; PMID:23303309; http://dx.doi.org/10.1098/rsob.120144
76. Tamada M, Nagano O, Tateyama S, Ohmura M, Yae T, Ishimoto T, Sugihara E, Onishi N, Yamamoto T, Yanagawa H, et al. Modulation of glucose metabolism by CD44 contributes to antioxidant status and drug resistance in cancer cells. Cancer Res 2012; 72:14-38 48; PMID:22293754; http://dx.doi.org/10.1158/0008-5472.CAN-11-3024
77. Croker AK, Allan AL. Inhibition of aldehyde de hydro-genase (ALDH) activity reduces chemotherapy and radiation resistance of stem-like ALDHhiCD44+ human breast cancer cells. Breast Cancer Res Treat 2012; 133:75-87; PMID:21818590; http://dx.doi.org/10.1007/s10549-011-1692-y
78. Pani G, Galeotti T, Chiarugi P. Metastasis: cancer cell's escape from oxidative stress. Cancer Metastasis Rev 2010; 29:351-78; PMID:20386957; http://dx.doi.org/10.1007/s10555-010-9225-4
79. Boivin A, Hanot M, Malesys C, Maalouf M, Rousson R, Rodriguez-Lafrasse C, Ardail D. Transient alteration of cellular redox buffering before irradiation triggers apo-ptosis in head and neck carcinoma stem and non-stem cells. PLoS One 2011; 6:e14558; PMID:21283807; http://dx.doi.org/10.1371/journal.pone.0014558
80. Pei S, Minhajuddin M, Callahan KP, Balys M, Ashton JM, Neering SJ, Lagadinou ED, Corbett C, Ye H, Lies-veld JL, et al. Targeting aberrant glutathione metabolism to eradicate human acute myelogenous leukemia cells. J Biol Chem 2013; 288:33542-58; PMID:24089526; http://dx.doi.org/10.1074/jbc.M113.511170
81. Kawamura T, Kondoh Y, Muroi M, Kawatani M, Osada H. A small molecule that induces reactive oxygen species via cellular glutathione depletion. Biochem J 2014; 463:53-63; PMID:25011393; http://dx.doi.org/10.1042/BJ20140669
82. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB. 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; 104:19345-50; PMID:18032601;http://dx.doi.org/10.1073/pnas.0709747104
83. Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 2007; 7:763-77; PMID:17882277; http://dx.doi.org/10.1038/nrc2222
84. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 32:1029-33; PMID:19460998; http://dx.doi.org/10.1126/science.1160809
85. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogram-ming fuels cell growth and proliferation. Cell Metab 2008; 7:11-20; PMID:18177721; http://dx.doi.org/10.1016/j.cmet.2007.10.002
86. Shiraki N, Shiraki Y, Tsuyama T, Obata F, Miura M, Nagae G, Aburatani H, Kume K, Endo F, Kume S. Methionine metabolism regulates maintenance and differentiation of human pluripotent stem cells. Cell Metab 2014; 19:780-94; PMID:24746804; http://dx.doi.org/10.1016/j.cmet.2014.03.017
87. Shyh-Chang N, Locasale JW, Lyssiotis CA, Zheng Y, Teo RY, Ratanasirintrawoot S, Zhang J, Onder T, Unternaehrer JJ, Zhu H, et al. Influence of threonine metabolism on S-adenosylmethionine and histone meth ylation. Science 2013; 339:222-6; PMID:23118012; http://dx.doi.org/10.1126/science.1226603
88. Lu C, Thompson CB. Metabolic regulation of epige netics. Cell Metab 2012; 16:9-17; PMID:22768835; http://dx.doi.org/10.1016/j.cmet.2012.06.001
89. Locasale JW. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer 2013; 13:572-83; PMID:23822983; http://dx.doi.org/10.1038/nrc3557
90. Johnson C, Warmoes MO, Shen X, Locasale JW. Epi genetics and cancer metabolism. Cancer Lett 2015; 356:309-14; PMID:24125862; http://dx.doi.org/10.1016/j.canlet.2013.09.043
91. Li G, Zhao F, Cui Y. Proteomics using mammo-spheres as a model system to identify proteins deregulated in breast cancer stem cells. Curr Mol Med 2013; 13:459-463; PMID:23331018
92. Pandey PR, Xing F, Sharma S, Watabe M, Pai SK, Iii-zumi-Gairani M, Fukuda K, Hirota S, Mo YY, Watabe K. Elevated lipogenesis in epithelial stem-like cell confers survival advantage in ductal carcinoma in situ of breast cancer. Oncogene2013; 32:5111-22; PMID:23208501; http://dx.doi.org/10.1038/onc.2012.519
93. Pandey PR, Okuda H, Watabe M, Pai SK, Liu W, Kobayashi A, Xing F, Fukuda K, Hirota S, Sugai T, et al. Resveratrol suppresses growth of cancer stemlike cells by inhibiting fatty acid synthase. Breast Cancer Res Treat 2011; 130:387-98; PMID:21188630; http://dx.doi.org/10.1007/s10549-010-1300-6
94. Corominas-Faja B, Cuyas E, Gumuzio J, Bosch-Bar-rera J, Leis O, Martin Ao G, Menendez JA. Chemical inhibition of acetyl-CoA carboxylase suppresses self-renewal growth of cancer stem cells. Oncotarget 2014; 5:8306-16; PMID:25246709
95. Nomura DK, Long JZ, Niessen S, Hoover HS, Ng SW, Cravatt BF. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell 2010; 140:49-61; PMID:20079333; http://dx.doi.org/10.1016/j.cell.2009.11.027
96. Louie SM, Roberts LS, Mulvihill MM, Luo K, Nomura DK. Cancer cells incorporate and remodel exogenous palmitate into structural and oncogenic signaling lipids. Biochim Biophys Acta 2013; 1831:1566-72; PMID:23872477; http://dx.doi.org/10.1016/j.bbalip.2013.07.008
97. Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 2005; 8:299-309; PMID:16226705; http://dx.doi.org/10.1016/j.ccr.2005.09.005
98. Shen R, Ye Y, Chen L, Yan Q, Barsky SH, Gao JX. Pre-cancerous stem cells can serve as tumor vasculogenic progenitors. PLoS One 2008; 3:e1652; PMID:18286204; http://dx.doi.org/10.1371/journal.pone.0001652
99. Cabarcas SM, Mathews LA, Farrar WL. The cancer stem cell niche—there goes the neighborhood? Int J Cancer 2011; 129:2315-27; PMID:21792897; http://dx.doi.org/10.1002/ijc.26312
100. Cascone T, Herynk MH, Xu L, Du Z, Kadara H, Nilsson MB, Oborn CJ, Park YY, Erez B, Jacoby JJ, et al. Upregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitor-resistant human lung adenocarcinoma. J Clin Invest 2011; 121:1313-28; PMID:21436589; http://dx.doi.org/10.1172/JCI42405
101. Osawa T, Shibuya M. Targeting cancer cells resistant to hypoxia and nutrient starvation to improve anti-angiogeneic therapy. Cell Cycle 2013; 12:2519-20; PMID:23907114; http://dx.doi.org/10.4161/cc.25729
102. Philip B, Ito K, Moreno-Soanchez R, Ralph SJ. HIF expression and the role of hypoxic microenvironments within primary tumours as protective sites driving cancer stem cell renewal and metastatic progression. Car-cinogenesis 2013; 34:1699-707; PMID:23740838; http://dx.doi.org/10.1093/carcin/bgt209
103. Mathonnet M, Perraud A, Christou N, Akil H, Melin C, Battu S, Jauberteau MO, Denizot Y. Hallmarks in colorectal cancer: Angiogenesis and cancer stem-like cells. World J Gastroenterol 2014; 20:4189-96; PMID:24764657; http://dx.doi.org/10.3748/wjg.v20.i15.4189
104. Sounni NE, Cimino J, Blacher S, Primac I, Truong A, Mazzucchelli G, Paye A, Calligaris D, Debois D, De Tul-lio P, et al. Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal. Cell Metab 2014; 20:280-94; PMID:25017943; http://dx.doi.org/10.1016/j.cmet.2014.05.022
105. Menendez JA, Joven J. Energy metabolism and metabolic sensors in stem cells: the metabostem crossroads of aging and cancer. Adv Exp Med Biol 2014; 824:117-40; PMID:25038997; http://dx.doi.org/10.1007/978-3-319-07320-0_10
106. Chen T, Shen L, Yu J, Wan H, Guo A, Chen J, Long Y, Zhao J, Pei G. Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells. Aging Cell 10:908-11; PMID:21615676; http://dx.doi.org/10.1111/j.1474-9726.2011.00722.x
107. Easley CA 4th, Ben-Yehudah A, Redinger CJ, Oliver SL, Varum ST, Eisinger VM, Carlisle DL, Donovan PJ, Schatten GP. mTOR-mediated activation of p70 S6K induces differentiation of pluripotent human embryonic stem cells. Cell Reprogram 2010; 12:26373; PMID:20698768; http://dx.doi.org/10.1089/cell.2010.0011
108. He J, Kang L, Wu T, Zhang J, Wang H, Gao H, Zhang Y, Huang B, Liu W, Kou Z, et al. An elaborate regulation of Mammalian target of rapamycin activity is required for somatic cell reprogramming induced by defined transcription factors. Stem Cells Dev 21:2630-41; PMID:22471963; http://dx.doi.org/10.1089/scd.2012.0015
109. Wang S, Xia P, Ye B, Huang G, Liu J, Fan Z. Transient activation of autophagy via Sox2-mediated suppression of mTOR is an important early step in reprogramming to pluripotency. Cell Stem Cell 2013; 13:617-25; PMID:24209762; http://dx.doi.org/10.1016/j.stem.2013.10.005
110. Vazquez-Martin A, Vellon L, Quiroos PM, Cufo S, Ruiz de Galarreta E, Oliveras-Ferraros C, Martin AG, Martin-Castillo B, Loopez-Oton C, et al. Activation of AMP-activated protein kinase (AMPK) provides a metabolic barrier to reprogramming somatic cells into stem cells. Cell Cycle 2012; 11:974-89; PMID:22333578; http://dx.doi.org/10.4161/cc.11.5.19450
111. Vazquez-Martin A, Cufi S, Lopez-Bonet E, Coromi-nas-Faja B, Oliveras-Ferraros C, Martin-Castillo B, Menendez JA. Metformin limits the tumourigenicity of iPS cells without affecting their pluripotency. Sci Rep 2012; 2:964; PMID:23236586; http://dx.doi.org/10.1038/srep00964
112. Jung JW, Park SB, Lee SJ, Seo MS, Trosko JE, Kang KS. Metformin represses self-renewal of the human breast carcinoma stem cells via inhibition of estrogen receptor-mediated OCT4 expression. PLoS One 2011; 6:e28068; PMID:22132214; http://dx.doi.org/10.1371/journal.pone.0028068
113. Pollak M. Potentialapplicationsforbiguanidesinoncology. J Clin Invest 2013; 123: 3693-700; PMID:23999444; http://dx.doi.org/10.1172/JCI67232
114. Iliopoulos D, Hirsch HA, Wang G, Struhl K. Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc Natl Acad Sci U S A 2011; 108:1397-402; PMID:21220315; http://dx.doi.org/10.1073/pnas.1018898108
115. Hirsch HA, Iliopoulos D, Struhl K. Metformininhib-its the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc Natl Acad Sci U S A 2013; 110:972-7; PMID:23277563; http://dx.doi.org/10.1073/pnas.1221055110
116. Janzer A, German NJ, Gonzalez-Herrera KN, Asara JM, Haigis MC, Struhl K. Metformin and phenfor-min deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells. Proc Natl Acad Sci U S A 2014; 111:10574-9; PMID:25002509; http://dx.doi.org/10.1073/pnas.1409844111
117. Del Barco S, Vazquez-Martin A, Cufo S, Oliveras-Fer-raros C, Bosch-Barrera J, Joven J, Martin-Castillo B, Menendez JA. Metformin: multi-faceted protection against cancer. Oncotarget 2011; 2:896-917; PMID:22203527
118. Waddington CH. The strategy of the genes. London, UK: AllenandUnwin; 1957.
119. Huang S. Reprogramming cell fates: reconciling rarity with robustness. Bioessays 2009; 31:546-60; PMID:19319911; http://dx.doi.org/10.1002/bies.200800189
120. Huang S. Systems biology of stem cells: three useful perspectives to help overcome the paradigm of linear pathways. Philos Trans R Soc Lond B Biol Sci 2011; 366:2247-59; PMID:21727130; http://dx.doi.org/10.1098/rstb.2011.0008
121. Hou P, Li Y, Zhang X, Liu C, Guan J, Li H, Zhao T, Ye J, Yang W, Liu K, et al. Pluripotent stem cells induced from mouse somatic cells bysmall-molecule compounds. Science 2013; 41:651-4; PMID:23868920; http://dx.doi.org/10.1126/science.1239278
122. Menendez JA, Alarcoon T. Metabostemness: A new cancer hallmark. Front Oncol 2014; 4:262; PMID:25325014; http://dx.doi.org/10.3389/fonc.2014.00262
123. Huang S, Ernberg I, Kauffman S. Cancer attractors: a systems view of tumors from a gene network dynamics and developmental perspective. Semin Cell Dev Biol 2009; 20:869-876; PMID:19595782; http://dx.doi.org/10.1016/j.semcdb.2009.07.003
124. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, Cross JR, Fantin VR, Hedvat CV, Perl AE, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 2010; 17:225-34; PMID:20171147; http://dx.doi.org/10.1016/j.ccr.2010.01.020
125. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S, Yang C, Wang P, Xiao MT, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of a-ketoglutarate-dependent dioxygenases. Cancer Cell 2011; 19:17-30; PMID:21251613; http://dx.doi.org/10.1016/j.ccr.2010.12.014
126. Chowdhury R, Yeoh KK, Tian YM, Hillringhaus L, Bagg EA, Rose NR, Leung IK, Li XS, Woon EC, Yang M, et al. The oncometabolite 2-hydroxygluta-rate inhibits histone lysine demethylases. EMBO Rep 2011; 12:463-9; PMID:21460794; http://dx.doi.org/10.1038/embor.2011.43
127. Yang M, Soga T, Pollard PJ. Oncometabolites: linking altered metabolism with cancer. J Clin Invest 2013; 123:3652-8; PMID:23999438; http://dx.doi.org/10.1172/JCI67228
128. Cairns RA, Mak TW. Oncogenic isocitrate dehydroge-nase mutations: mechanisms, models, and clinical opportunities. Cancer Discov 2013; 3:730-41; PMID:23796461; http://dx.doi.org/10.1158/2159-8290.CD-13-0083
129. Krell D, Mulholland P, Frampton AE, Krell J, Stebbing J, Bardella C. IDH mutations in tumorigenesis and their potential role as novel therapeutic targets. Future Oncol 2013; 9:1923-35; PMID:24295421; http://dx.doi.org/10.2217/fon.13.143
130. Menendez JA, Alarcoon T, Joven J. Gerometabolites: the pseudohypoxic aging side of cancer oncometabolites. Cell Cycle 2014; 13:699-709; PMID:24526120; http://dx.doi.org/10.4161/cc.28079
131. Terunuma A, Putluri N, Mishra P, Mathoe EA, Dorsey TH, Yi M, Wallace TA, Issaq HJ, Zhou M, Killian JK, et al. MYC-driven accumulation of 2-hydroxyglu-tarate is associated with breast cancer prognosis. J Clin Invest 2014; 124: 398-412; PMID:24316975; http://dx.doi.org/10.1172/JCI71180
132. Saha SK, Parachoniak CA, Ghanta KS, Fitamant J, Ross KN, Najem MS, Gurumurthy S, Akbay EA, Sia D, et al. Mutant IDH inhibits HNF-4a to block hepa-tocyte differentiation and promote biliary cancer. Nature 2014; 513:110-4; PMID:25043045; http://dx.doi.org/10.1038/nature13441
133. Hanna JH, Saha K, Jaenisch R. Pluripotency and cellular reprogramming: facts, hypotheses, unresolved issues. Cell 2010; 143:508-25; PMID:21074044; http://dx.doi.org/10.1016/j.cell.2010.10.008
134. Huang S. The molecular and mathematical basis of Waddington's epigenetic landscape: a framework for post-Darwinian biology? Bioessays 2012; 34:149-57; PMID:22102361; http://dx.doi.org/10.1002/bies.201100031
135. Menendez JA, Corominas-Faja B, Cuyas E, Alarcon T. Metabostemness: Metaboloepigenetic reprogram-ming of cancer stem-cell functions. 2015; 1:803-6. PMID: 25621295
136. Cufo S, Vazquez-Martin A, Oliveras-Ferraros C, Martin-Castillo B, Vellon L, Menendez JA. Autophagy positively regulates the CD44(C) CD24(-/low) breast cancer stem-like phenotype. Cell Cycle 2011; 10:3871-85; PMID:22127234; http://dx.doi.org/10.4161/cc.10.22.17976
137. Guan JL, Simon AK, Prescott M, Menendez JA, Liu F, Wang F, Wang C, Wolvetang E, Vazquez-Martin A, Zhang J. Autophagy in stem cells. Autophagy 2013; 9:830-49; PMID:23486312; http://dx.doi.org/10.4161/auto.24132
138. Stem Cell Energetics. 2014; 15:679-82; http://dx.doi.org/10.1016/j.stem.2014.11.013
139. Cuyas E, Corominas-Faja B, Menendez JA. The nutritional phenome of EMT-induced cancer stem-like cells. Oncotarget 2014; 5:3970-82; PMID:24994116
140. Prigione A, Ruiz-Poerez MV, Bukowiecki R, Adjaye J. Metabolic restructuring and cell fate conversion. Cell Mol Life Sci 2015 Jan 14. [Epub ahead of print]; PMID:25586562
141. Teslaa T, Teitell MA. Pluripotent stem cell energy metabolism: an update. EMBO J 2015; 34:138-153; PMID:25476451; http://dx.doi.org/10.15252/embj.201490446
142. Apostolou E, Hochedlinger K. Chromatin dynamics during cellular reprogramming. Nature 2013; 502:462-71; PMID:24153299; http://dx.doi.org/10.1038/nature12749
143. Zviran A, Hanna JH. Lucky iPSCs. Genome Biol 2014; 15:109; PMID:25002192; http://dx.doi.org/10.1186/gb4167
144. Teicher BA, Linehan WM, Helman LJ. Targeting cancer metabolism. Clin Cancer Res. 2012; 18:5537-45; PMID:23071355; http://dx.doi.org/10.1158/1078-0432.CCR-12-2587
145. Galluzzi L, Kepp O, Vander Heiden MG, Kroemer G. Metabolic targets for cancer therapy. Nat Rev Drug Discov2013; 12:829-46; PMID:24113830; http://dx.doi.org/10.1038/nrd4145
146. DeLaBarre B, Hurov J, Cianchetta G, Murray S, Dang L. Action at a distance: allostery and the development of drugs to target cancer cell metabolism. Chem Biol 2014; 21:1143-61; PMID:25237859; http://dx.doi.org/10.1016/j.chembiol.2014.08.007