Cancer stem cells and Epithelial-to-Mesenchymal Transition (EMT)-Phenotypic Cells: Are they Cousins or Twins?

Cancers

Volumn 3, Issue 1, 2011, Pages 716-729

  Kong, Dejuan ^a   Li, Yiwei ^a   Wang, Zhiwei ^a   Sarkar, Fazlul H ^a  

^a WAYNE STATE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Cancer stem like cells; Drug resistant; Epithelial to Mesenchymal Transition; Tumor initiating cells

Indexed keywords

MICRORNA; MICRORNA 183; MICRORNA 200A; MICRORNA 200B; MICRORNA 200C; MICRORNA 203; NOTCH1 RECEPTOR; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG; WNT PROTEIN;

BREAST CANCER; CANCER CELL; CANCER GROWTH; CANCER INVASION; CANCER RECURRENCE; CANCER STAGING; CANCER STEM CELL; CARCINOGENESIS; CARCINOMA; CELL DIFFERENTIATION; CELL RENEWAL; EARLY CANCER; EPITHELIAL MESENCHYMAL TRANSITION; EPITHELIUM CELL; HUMAN; MESENCHYME CELL; METASTASIS; NONHUMAN; PANCREAS CANCER; PHENOTYPE; PROSTATE CANCER; REVIEW; SOLID TUMOR;

EID: 79953689605     PISSN: None     EISSN: 20726694     Source Type: Journal    
DOI: 10.3390/cancers30100716     Document Type: Review

References (82)

1. Thiery, J.P. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2002, 2, 442-454.
2. Brabletz, T.; Jung, A.; Reu, S.; Porzner, M.; Hlubek, F.; Kunz-Schughart, L.A.; Knuechel, R.; Kirchner, T. Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc. Natl. Acad. Sci. USA 2001, 98, 10356-10361.
3. Brabletz, T.; Jung, A.; Spaderna, S.; Hlubek, F.; Kirchner, T. Opinion: Migrating cancer stem cells-An integrated concept of malignant tumour progression. Nat. Rev. Cancer 2005, 5, 744-749.
4. Lee, J.M.; Dedhar, S.; Kalluri, R.; Thompson, E.W. The epithelial-mesenchymal transition: New insights in signaling, development, and disease. J. Cell Biol. 2006, 172, 973-981.
5. Hollier, B.G.; Evans, K.; Mani, S.A. The epithelial-to-mesenchymal transition and cancer stem cells: A coalition against cancer therapies. J. Mammary. Gland. Biol. Neoplasia 2009, 14, 29-43.
6. Kasper, S. Stem cells: The root of prostate cancer? J. Cell Physiol. 2008, 216, 332-336.
7. Kasper, S. Identification, characterization, and biological relevance of prostate cancer stem cells from clinical specimens. Urol. Oncol. 2009, 27, 301-303.
8. Marian, C.O.; Shay, J.W. Prostate tumor-initiating cells: A new target for telomerase inhibition therapy? Biochim. Biophys. Acta 2009, 1792, 289-296.
9. Mani, S.A.; Guo, W.; Liao, M.J.; Eaton, E.N.; Ayyanan, A.; Zhou, A.Y.; Brooks, M.; Reinhard, F.; Zhang, C.C.; Shipitsin, M.; Campbell, L.L.; Polyak, K.; Brisken, C.; Yang, J.; Weinberg, R.A. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008, 133, 704-715.
10. Peter, M.E. Let-7 and miR-200 microRNAs: Guardians against pluripotency and cancer progression. Cell Cycle 2009, 8, 843-852.
11. Santisteban, M.; Reiman, J.M.; Asiedu, M.K.; Behrens, M.D.; Nassar, A.; Kalli, K.R.; Haluska, P.; Ingle, J.N.; Hartmann, L.C.; Manjili, M.H.; Radisky, D.C.; Ferrone, S.; Knutson, K.L. Immune-induced epithelial to mesenchymal transition in vivo generates breast cancer stem cells. Cancer Res. 2009, 69, 2887-2895.
12. Hugo, H.; Ackland, M.L.; Blick, T.; Lawrence, M.G.; Clements, J.A.; Williams, E.D.; Thompson, E.W. Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression. J. Cell Physiol. 2007, 213, 374-383.
13. Sarkar, F.H.; Li, Y.; Wang, Z.; Kong, D. The role of nutraceuticals in the regulation of Wnt and Hedgehog signaling in cancer. Cancer Metastasis Rev. 2010, 29, 383-394.
14. Singh, A.; Settleman, J. EMT, cancer stem cells and drug resistance: An emerging axis of evil in the war on cancer. Oncogene 2010, 29, 4741-4751.
15. Wang, Z.; Li, Y.; Ahmad, A.; Azmi, A.S.; Kong, D.; Banerjee, S.; Sarkar, F.H. Targeting miRNAs involved in cancer stem cell and EMT regulation: An emerging concept in overcoming drug resistance. Drug Resist. Updat. 2010, 13, 109-118.
16. Thiery, J.P.; Sleeman, J.P. Complex networks orchestrate epithelial-mesenchymal transitions. Nat. Rev. Mol. Cell Biol. 2006, 7, 131-142.
17. Schmalhofer, O.; Brabletz, S.; Brabletz, T. E-cadherin, beta-catenin, and ZEB1 in malignant progression of cancer. Cancer Metastasis Rev. 2009, 28, 151-166.
18. Berx, G.; Raspe, E.; Christofori, G.; Thiery, J.P.; Sleeman, J.P. Pre-EMTing metastasis? Recapitulation of morphogenetic processes in cancer. Clin. Exp. Metastasis. 2007, 24, 587-597.
19. Gregory, P.A.; Bert, A.G.; Paterson, E.L.; Barry, S.C.; Tsykin, A.; Farshid, G.; Vadas, M.A.; Khew-Goodall, Y.; Goodall, G.J. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat. Cell Biol. 2008, 10, 593-601.
20. Kong, D.; Wang, Z.; Sarkar, S.H.; Li, Y.; Banerjee, S.; Saliganan, A.; Kim, H.R.; Cher, M.L.; Sarkar, F.H. Platelet-derived growth factor-D overexpression contributes to epithelialmesenchymal transition of PC3 prostate cancer cells. Stem Cells 2008, 26, 1425-1435.
21. Shorning, B.Y.; Griffiths, D.; Clarke, A.R. Lkb1 and Pten Synergise to Suppress mTOR-Mediated Tumorigenesis and Epithelial-Mesenchymal Transition in the Mouse Bladder. PLoS One 2011, 6, e16209.
22. Christiansen, J.J.; Rajasekaran, A.K. Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res. 2006, 66, 8319-8326.
23. Garber, K. Epithelial-to-mesenchymal transition is important to metastasis, but questions remain. J. Natl. Cancer Inst. 2008, 100, 232-3, 239.
24. Tarin, D.; Thompson, E.W.; Newgreen, D.F. The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res. 2005, 65, 5996-6000.
25. Thompson, E.W.; Newgreen, D.F.; Tarin, D. Carcinoma invasion and metastasis: A role for epithelial-mesenchymal transition? Cancer Res. 2005, 65, 5991-5995.
26. Aigner, K.; Dampier, B.; Descovich, L.; Mikula, M.; Sultan, A.; Schreiber, M.; Mikulits, W.; Brabletz, T.; Strand, D.; Obrist, P.; Sommergruber, W.; Schweifer, N.; Wernitznig, A.; Beug, H.; Foisner, R.; Eger, A. The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene. 2007, 26, 6979-6988.
27. Chaffer, C.L.; Brennan, J.P.; Slavin, J.L.; Blick, T.; Thompson, E.W.; Williams, E.D. Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: Role of fibroblast growth factor receptor-2. Cancer Res. 2006, 66, 11271-11278.
28. Irie, H.Y.; Pearline, R.V.; Grueneberg, D.; Hsia, M.; Ravichandran, P.; Kothari, N.; Natesan, S.; Brugge, J.S. Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelialmesenchymal transition. J. Cell Biol. 2005, 171, 1023-1034.
29. Moustakas, A.; Heldin, C.H. Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci. 2007, 98, 1512-1520.
30. Yates, C.C.; Shepard, C.R.; Stolz, D.B.; Wells, A. Co-culturing human prostate carcinoma cells with hepatocytes leads to increased expression of E-cadherin. Br. J. Cancer 2007, 96, 1246-1252.
31. Ahmed, N.; Maines-Bandiera, S.; Quinn, M.A.; Unger, W.G.; Dedhar, S.; Auersperg, N. Molecular pathways regulating EGF-induced epithelio-mesenchymal transition in human ovarian surface epithelium. Am. J. Physiol Cell Physiol. 2006, 290, C1532-C1542.
32. Fischer, A.N.; Fuchs, E.; Mikula, M.; Huber, H.; Beug, H.; Mikulits, W. PDGF essentially links TGF-beta signaling to nuclear beta-catenin accumulation in hepatocellular carcinoma progression. Oncogene 2007, 26, 3395-3405.
33. Gotzmann, J.; Fischer, A.N.; Zojer, M.; Mikula, M.; Proell, V.; Huber, H.; Jechlinger, M.; Waerner, T.; Weith, A.; Beug, H.; Mikulits, W. A crucial function of PDGF in TGF-betamediated cancer progression of hepatocytes. Oncogene 2006, 25, 3170-3185.
34. Strutz, F.; Zeisberg, M.; Ziyadeh, F.N.; Yang, C.Q.; Kalluri, R.; Muller, G.A.; Neilson, E.G. Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int. 2002, 61, 1714-1728.
35. Yang, L.; Lin, C.; Liu, Z.R. P68 RNA helicase mediates PDGF-induced epithelial mesenchymal transition by displacing Axin from beta-catenin. Cell 2006, 127, 139-155.
36. Graham, T.R.; Zhau, H.E.; Odero-Marah, V.A.; Osunkoya, A.O.; Kimbro, K.S.; Tighiouart, M.; Liu, T.; Simons, J.W.; O'Regan, R.M. Insulin-like growth factor-I-dependent up-regulation of ZEB1 drives epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer Res. 2008, 68, 2479-2488.
37. Lapidot, T.; Sirard, C.; Vormoor, J.; Murdoch, B.; Hoang, T.; Caceres-Cortes, J.; Minden, M.; Paterson, B.; Caligiuri, M.A.; Dick, J.E. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994, 367, 645-648.
38. Al-Hajj, M.; Wicha, M.S.; Ito-Hernandez, A.; Morrison, S.J.; Clarke, M.F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. USA 2003, 100, 3983-3988.
39. O'Brien, C.A.; Pollett, A.; Gallinger, S.; Dick, J.E. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007, 445, 106-110.
40. Ricci-Vitiani, L.; Lombardi, D.G.; Pilozzi, E.; Biffoni, M.; Todaro, M.; Peschle, C.; De, M.R. Identification and expansion of human colon-cancer-initiating cells. Nature 2007, 445, 111-115.
41. Singh, S.K.; Hawkins, C.; Clarke, I.D.; Squire, J.A.; Bayani, J.; Hide, T.; Henkelman, R.M.; Cusimano, M.D.; Dirks, P.B. Identification of human brain tumour initiating cells. Nature 2004, 432, 396-401.
42. Singh, S.K.; Clarke, I.D.; Terasaki, M.; Bonn, V.E.; Hawkins, C.; Squire, J.; Dirks, P.B. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003, 63, 5821-5828.
43. Collins, A.T.; Berry, P.A.; Hyde, C.; Stower, M.J.; Maitland, N.J. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005, 65, 10946-10951.
44. Patrawala, L.; Calhoun, T.; Schneider-Broussard, R.; Li, H.; Bhatia, B.; Tang, S.; Reilly, J.G.; Chandra, D.; Zhou, J.; Claypool, K.; Coghlan, L.; Tang, D.G. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 2006, 25, 1696-1708.
45. Roudier, M.P.; True, L.D.; Higano, C.S.; Vesselle, H.; Ellis, W.; Lange, P.; Vessella, R.L. Phenotypic heterogeneity of end-stage prostate carcinoma metastatic to bone. Hum. Pathol. 2003, 34, 646-653.
46. Gu, G.; Yuan, J.; Wills, M.; Kasper, S. Prostate cancer cells with stem cell characteristics reconstitute the original human tumor in vivo. Cancer Res. 2007, 67, 4807-4815.
47. Klarmann, G.J.; Hurt, E.M.; Mathews, L.A.; Zhang, X.; Duhagon, M.A.; Mistree, T.; Thomas, S.B.; Farrar, W.L. Invasive prostate cancer cells are tumor initiating cells that have a stem cell-like genomic signature. Clin. Exp. Metastasis. 2009, 26, 433-446.
48. Aoi, T.; Yae, K.; Nakagawa, M.; Ichisaka, T.; Okita, K.; Takahashi, K.; Chiba, T.; Yamanaka, S. Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science 2008, 321, 699-702.
49. Yu, J.; Vodyanik, M.A.; Smuga-Otto, K.; Ntosiewicz-Bourget, J.; Frane, J.L.; Tian, S.; Nie, J.; Jonsdottir, G.A.; Ruotti, V.; Stewart, R.; Slukvin, I.I.; Thomson, J.A. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007, 318, 1917-1920.
50. Yu, J.; Hu, K.; Smuga-Otto, K.; Tian, S.; Stewart, R.; Slukvin, I.I.; Thomson, J.A. Human induced pluripotent stem cells free of vector and transgene sequences. Science 2009, 324, 797-801.
51. Ben-Porath, I.; Thomson, M.W.; Carey, V.J.; Ge, R.; Bell, G.W.; Regev, A.; Weinberg, R.A. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat. Genet. 2008, 40, 499-507.
52. Jeter, C.R.; Badeaux, M.; Choy, G.; Chandra, D.; Patrawala, L.; Liu, C.; Calhoun-Davis, T.; Zaehres, H.; Daley, G.Q.; Tang, D.G. Functional evidence that the self-renewal gene NANOG regulates human tumor development. Stem Cells 2009, 27, 993-1005.
53. Lu, Y.; Futtner, C.; Rock, J.R.; Xu, X.; Whitworth, W.; Hogan, B.L.; Onaitis, M.W. Evidence that SOX2 overexpression is oncogenic in the lung. PLoS One 2010, 5, e11022.
54. Sholl, L.M.; Barletta, J.A.; Yeap, B.Y.; Chirieac, L.R.; Hornick, J.L. Sox2 protein expression is an independent poor prognostic indicator in stage I lung adenocarcinoma. Am. J. Surg. Pathol. 2010, 34, 1193-1198.
55. Sotomayor, P.; Godoy, A.; Smith, G.J.; Huss, W.J. Oct4A is expressed by a subpopulation of prostate neuroendocrine cells. Prostate 2009, 69, 401-410.
56. Thiery, J.P.; Acloque, H.; Huang, R.Y.; Nieto, M.A. Epithelial-mesenchymal transitions in development and disease. Cell 2009, 139, 871-890.
57. Tomaskovic-Crook, E.; Thompson, E.W.; Thiery, J.P. Epithelial to mesenchymal transition and breast cancer. Breast Cancer Res. 2009, 11, 213.
58. Blick, T.; Hugo, H.; Widodo, E.; Waltham, M.; Pinto, C.; Mani, S.A.; Weinberg, R.A.; Neve, R.M.; Lenburg, M.E.; Thompson, E.W. Epithelial mesenchymal transition traits in human breast cancer cell lines parallel the CD44(hi/)CD24 (lo/-) stem cell phenotype in human breast cancer. J. Mammary. Gland. Biol. Neoplasia 2010, 15, 235-252.
59. Caja, L.; Bertran, E.; Campbell, J.; Fausto, N.; Fabregat, I. The transforming growth factor-beta (TGF-beta) mediates acquisition of a mesenchymal stem cell-like phenotype in human liver cells. J. Cell Physiol. 2010, DOI:10.1002/jcp.22439.
60. Fuxe, J.; Vincent, T.; de Herreros, A.G. Transcriptional crosstalk between TGFbeta and stem cell pathways in tumor cell invasion: Role of EMT promoting Smad complexes. Cell Cycle 2010, 9, 2363-2374.
61. Martin, A.; Cano, A. Tumorigenesis: Twist1 links EMT to self-renewal. Nat. Cell Biol. 2010, 12, 924-925.
62. Phinney, D.G. Twist, Epithelial-to-Mesenchymal Transition, and Stem Cells. Stem Cells 2011, 29, 3-4.
63. Yang, M.H.; Hsu, D.S.; Wang, H.W.; Wang, H.J.; Lan, H.Y.; Yang, W.H.; Huang, C.H.; Kao, S.Y.; Tzeng, C.H.; Tai, S.K.; Chang, S.Y.; Lee, O.K.; Wu, K.J. Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat. Cell Biol. 2010, 12, 982-992.
64. Zavadil, J. A spotlight on regulatory networks connecting EMT and cancer stem cells. Cell Cycle 2010, 9, 2927.
65. Morel, A.P.; Lievre, M.; Thomas, C.; Hinkal, G.; Ansieau, S.; Puisieux, A. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One 2008, 3, e2888.
66. Gupta, P.B.; Onder, T.T.; Jiang, G.; Tao, K.; Kuperwasser, C.; Weinberg, R.A.; Lander, E.S. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 2009, 138, 645-659.
67. Sarkar, F.H.; Li, Y.; Wang, Z.; Kong, D.; Ali, S. Implication of microRNAs in drug resistance for designing novel cancer therapy. Drug Resist. Updat. 2010, 13, 57-66.
68. Cano, A.; Nieto, M.A. Non-coding RNAs take centre stage in epithelial-to-mesenchymal transition. Trends Cell Biol. 2008, 18, 357-359.
69. Garzon, R.; Fabbri, M.; Cimmino, A.; Calin, G.A.; Croce, C.M. MicroRNA expression and function in cancer. Trends Mol. Med. 2006, 12, 580-587.
70. Kong, D.; Li, Y.; Wang, Z.; Banerjee, S.; Ahmad, A.; Kim, H.R.; Sarkar, F.H. miR-200 Regulates PDGF-D-Mediated Epithelial-Mesenchymal Transition, Adhesion, and Invasion of Prostate Cancer Cells. Stem Cells 2009, 27, 1712-1721.
71. Korpal, M.; Lee, E.S.; Hu, G.; Kang, Y. The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J. Biol. Chem. 2008, 283, 14910-14914.
72. Li, Y.; VandenBoom, T.G.; Kong, D.; Wang, Z.; Ali, S.; Philip, P.A.; Sarkar, F.H. Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Cancer Res. 2009, 69, 6704-6712.
73. Park, S.M.; Gaur, A.B.; Lengyel, E.; Peter, M.E. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 2008, 22, 894-907.
74. Burk, U.; Schubert, J.; Wellner, U.; Schmalhofer, O.; Vincan, E.; Spaderna, S.; Brabletz, T. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 2008, 9, 582-589.
75. Kong, D.; Banerjee, S.; Ahmad, A.; Li, Y.; Wang, Z.; Sethi, S.; Sarkar, F.H. Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS One 2010, 5, e12445.
76. Shimono, Y.; Zabala, M.; Cho, R.W.; Lobo, N.; Dalerba, P.; Qian, D.; Diehn, M.; Liu, H.; Panula, S.P.; Chiao, E.; Dirbas, F.M.; Somlo, G.; Pera, R.A.; Lao, K.; Clarke, M.F. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 2009, 138, 592-603.
77. Wellner, U.; Schubert, J.; Burk, U.C.; Schmalhofer, O.; Zhu, F.; Sonntag, A.; Waldvogel, B.; Vannier, C.; Darling, D.; zur, H.A.; Brunton, V.G.; Morton, J.; Sansom, O.; Schuler, J.; Stemmler, M.P.; Herzberger, C.; Hopt, U.; Keck, T.; Brabletz, S.; Brabletz, T. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat. Cell Biol. 2009, 11, 1487-1495.
78. Iliopoulos, D.; Polytarchou, C.; Hatziapostolou, M.; Kottakis, F.; Maroulakou, I.G.; Struhl, K.; Tsichlis, P.N. MicroRNAs differentially regulated by Akt isoforms control EMT and stem cell renewal in cancer cells. Sci. Signal. 2009, 2, ra62.
79. Iliopoulos, D.; Lindahl-Allen, M.; Polytarchou, C.; Hirsch, H.A.; Tsichlis, P.N.; Struhl, K. Loss of miR-200 inhibition of Suz12 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells. Mol. Cell 2010, 39, 761-772.
80. Boyer, L.A.; Plath, K.; Zeitlinger, J.; Brambrink, T.; Medeiros, L.A.; Lee, T.I.; Levine, S.S.; Wernig, M.; Tajonar, A.; Ray, M.K.; Bell, G.W.; Otte, A.P.; Vidal, M.; Gifford, D.K.; Young, R.A.; Jaenisch, R. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 2006, 441, 349-353.
81. Lee, T.I.; Jenner, R.G.; Boyer, L.A.; Guenther, M.G.; Levine, S.S.; Kumar, R.M.; Chevalier, B.; Johnstone, S.E.; Cole, M.F.; Isono, K.; Koseki, H.; Fuchikami, T.; Abe, K.; Murray, H.L.; Zucker, J.P.; Yuan, B.; Bell, G.W.; Herbolsheimer, E.; Hannett, N.M.; Sun, K.; Odom, D.T.; Otte, A.P.; Volkert, T.L.; Bartel, D.P.; Melton, D.A.; Gifford, D.K.; Jaenisch, R.; Young, R.A. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 2006, 125, 301-313.
82. Boyer, L.A.; Lee, T.I.; Cole, M.F.; Johnstone, S.E.; Levine, S.S.; Zucker, J.P.; Guenther, M.G.; Kumar, R.M.; Murray, H.L.; Jenner, R.G.; Gifford, D.K.; Melton, D.A.; Jaenisch, R.; Young, R.A. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 2005, 122, 947-956.