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  • Review Article
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The tumorigenicity of human embryonic and induced pluripotent stem cells

Nature Reviews Cancer volume 11, pages 268–277 (2011)Cite this article

Subjects

Key Points

  • Human embryonic stem cells (HESCs) share cellular and molecular phenotypes with tumour cells and cancer cell lines. When injected into immunodeficient mice, HESCs form teratomas. The tumorigenicity of HESCs is a major hurdle, which must be confronted before the achievements from this field of research can be safely translated into the clinic.

  • Sharing with HESCs their basic properties of self-renewal and pluripotency, human induced pluripotent stem cells (HiPSCs) also share their tumorigenic traits. However, HESCs and HiPSCs are not identical, and a rapidly accumulating body of work suggests considerable differences between these two pluripotent cell types.

  • The transcription factors commonly used for reprogramming somatic cells into HiPSCs (OCT4, SOX2, MYC and krupple-like factor 4 (KLF4)) are highly expressed in various types of cancer. HiPSCs are commonly derived using integrating vectors, thus creating a risk for genetic alterations and for reactivation of the reprogramming factors at later stages.

  • HiPSCs can acquire chromosomal aberrations, even more readily than HESCs. These can result from their somatic cells of origin, reprogramming stress and during culture adaptation. Aneuploidy of pluripotent stem cells has been suggested to increase their tumorigenicity.

  • Epigenetic differences between HESCs and HiPSCs also affect their tumorigenicity. The reprogramming process is often accompanied by epigenetic alterations. The epigenetic 'memory' of the cells might also contribute to their tumorigenicity.

  • Self-renewal is important for the tumorigenic traits of HESCs and HiPSCs, and cell cycle-related genes are crucial for an efficient reprogramming process. These genes are also involved in the genomic instability that characterizes pluripotent cells.

  • Owing to genetic and epigenetic causes, HiPSCs are more tumorigenic than HESCs, and harbour a risk for the development of teratocarcinomas and possibly somatic tumours.

  • In order to develop safe HESC- and HiPSC-based treatments, the tumorigenicity hurdle must be overcome. Three general strategies to cope with this risk have been suggested: terminal differentiation or complete elimination of residual pluripotent stem cells from culture; interfering with tumour-progression genes to prevent tumour formation from the residual pluripotent cells; and tumour detection and elimination after its initial formation in the patient's body.

Abstract

The unique abilities of human pluripotent stem cells to self-renew and to differentiate into cells of the three germ layers make them an invaluable tool for the future of regenerative medicine. However, the same properties also make them tumorigenic, and therefore hinder their clinical application. Hence, the tumorigenicity of human embryonic stem cells (HESCs) has been extensively studied. Until recently, it was assumed that human induced pluripotent stem cells (HiPSCs) would behave like their embryonic counterparts in respect to their tumorigenicity. However, a rapidly accumulating body of evidence suggests that there are important genetic and epigenetic differences between these two cell types, which seem to influence their tumorigenicity.

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Figure 1: Source of chromosomal aberrations in pluripotent stem cells.
Figure 2: Tumour formation in pluripotent stem cells.

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References

  1. Dreesen, O. & Brivanlou, A. H. Signaling pathways in cancer and embryonic stem cells. Stem Cell Rev. 3, 7–17 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Knoepfler, P. S. Deconstructing stem cell tumorigenicity: a roadmap to safe regenerative medicine. Stem Cells 27, 1050–1056 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Blum, B. & Benvenisty, N. The tumorigenicity of human embryonic stem cells. Adv. Cancer Res. 100, 133–158 (2008).References 2 and 3 are recent reviews on the tumorigenicity of HESCs and possible coping strategies.

    Article  PubMed  Google Scholar 

  4. Amit, M. et al. Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. Dev. Biol. 227, 271–278 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Baker, D. E. et al. Adaptation to culture of human embryonic stem cells and oncogenesis in vivo. Nature Biotech. 25, 207–215 (2007). Thorough overview of the chromosomal aberrations observed in HESCs in culture.

    Article  CAS  Google Scholar 

  7. Harrison, N. J., Baker, D. & Andrews, P. W. Culture adaptation of embryonic stem cells echoes germ cell malignancy. Int. J. Androl. 30, 275–281 (2007).

    Article  PubMed  Google Scholar 

  8. Hiyama, E. & Hiyama, K. Telomere and telomerase in stem cells. Br. J. Cancer 96, 1020–1024 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Eilers, M. & Eisenman, R. N. Myc's broad reach. Genes Dev. 22, 2755–2766 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Evans, P. M. & Liu, C. Roles of Krupel-like factor 4 in normal homeostasis, cancer and stem cells. Acta Biochim. Biophys. Sin. 40, 554–564 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Sperger, J. M. et al. Gene expression patterns in human embryonic stem cells and human pluripotent germ cell tumors. Proc. Natl Acad. Sci. USA 100, 13350–13355 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ben-Porath, I. et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nature Genet. 40, 499–507 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Wong, D. J. et al. Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell Stem Cell 2, 333–344 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Neveu, P. et al. MicroRNA profiling reveals two distinct p53-related human pluripotent stem cell states. Cell Stem Cell 7, 671–681 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Calvanese, V. et al. Cancer genes hypermethylated in human embryonic stem cells. PLoS ONE 3, e3294 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Bjorklund, L. M. et al. Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc. Natl Acad. Sci. USA 99, 2344–2349 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Herszfeld, D. et al. CD30 is a survival factor and a biomarker for transformed human pluripotent stem cells. Nature Biotech. 24, 351–357 (2006).

    Article  CAS  Google Scholar 

  18. Yang, S. et al. Tumor progression of culture-adapted human embryonic stem cells during long-term culture. Genes Chromosomes Cancer 47, 665–679 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Werbowetski-Ogilvie, T. E. et al. Characterization of human embryonic stem cells with features of neoplastic progression. Nature Biotech. 27, 91–97 (2009). First demonstration of altered proliferation and differentiation capacities in adapted HESC lines with subkaryotypic genetic abnormalities.

    Article  CAS  Google Scholar 

  20. Blum, B. & Benvenisty, N. The tumorigenicity of diploid and aneuploid human pluripotent stem cells. Cell Cycle 8, 3822–3830 (2009). Recent perspective of the tumorigenicity of HESCs and its relationship with genomic instability of HESCs in culture.

    Article  CAS  PubMed  Google Scholar 

  21. Martin, G. R. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc. Natl Acad. Sci. USA 78, 7634–7638 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Shih, C. C., Forman, S. J., Chu, P. & Slovak, M. Human embryonic stem cells are prone to generate primitive, undifferentiated tumors in engrafted human fetal tissues in severe combined immunodeficient mice. Stem Cells Dev. 16, 893–902 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Chin, M. H. et al. Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell 5, 111–123 (2009). First study describing global gene expression differences between HESCs and HiPSCs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Urbach, A., Bar-Nur, O., Daley, G. Q. & Benvenisty, N. Differential modeling of fragile X syndrome by human embryonic stem cells and induced pluripotent stem cells. Cell Stem Cell 6, 407–411 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Polo, J. M. et al. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nature Biotech. 28, 848–855 (2010).

    Article  CAS  Google Scholar 

  29. Kim, K. et al. Epigenetic memory in induced pluripotent stem cells. Nature 467, 285–290 (2010). References 28 and 29 are comprehensive studies describing epigenetic memory in mouse iPSCs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pick, M. et al. Clone- and gene-specific aberrations of parental imprinting in human induced pluripotent stem cells. Stem Cells 27, 2686–2690 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Albihn, A., Johnsen, J. I. & Henriksson, M. A. MYC in oncogenesis and as a target for cancer therapies. Adv. Cancer Res. 107, 163–224 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Ruggero, D. The role of Myc-induced protein synthesis in cancer. Cancer Res. 69, 8839–8843 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tian, Y. et al. MicroRNA-10b promotes migration and invasion through KLF4 in human esophageal cancer cell lines. J. Biol. Chem. 285, 7986–7994 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lambertini, C., Pantano, S. & Dotto, G. P. Differential control of Notch1 gene transcription by Klf4 and Sp3 transcription factors in normal versus cancer-derived keratinocytes. PLoS ONE 5, e10369 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Rageul, J. et al. KLF4-dependent, PPARγ-induced expression of GPA33 in colon cancer cell lines. Int. J. Cancer 125, 2802–2809 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Asadi, M. H. et al. OCT4B1, a novel spliced variant of OCT4, is highly expressed in gastric cancer and acts as an anti-apoptotic factor. Int. J. Cancer 3 Nov 2010 (doi:10.1002/ijc.25643).

  37. Wang, Y. et al. Oct-4B isoform is differentially expressed in breast cancer cells: hypermethylation of regulatory elements of Oct-4A suggests an alternative promoter and transcriptional start site for Oct-4B transcription. Biosci. Rep. 31, 109–115 (2010).

    Article  CAS  Google Scholar 

  38. Peng, S., Maihle, N. J. & Huang, Y. Pluripotency factors Lin28 and Oct4 identify a sub-population of stem cell-like cells in ovarian cancer. Oncogene 29, 2153–2159 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. 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. 34, 1193–1198 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Ji, J. & Zheng, P. S. Expression of Sox2 in human cervical carcinogenesis. Hum. Pathol. 41, 1438–1447 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. Schoenhals, M. et al. Embryonic stem cell markers expression in cancers. Biochem. Biophys. Res. Commun. 383, 157–162 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Ramos-Mejia, V., Munoz-Lopez, M., Garcia-Perez, J. L. & Menendez, P. iPSC lines that do not silence the expression of the ectopic reprogramming factors may display enhanced propensity to genomic instability. Cell Res. 20, 1092–1095 (2010).

    Article  PubMed  Google Scholar 

  43. Nakagawa, M. et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotech. 26, 101–106 (2008).

    Article  CAS  Google Scholar 

  44. Nakagawa, M., Takizawa, N., Narita, M., Ichisaka, T. & Yamanaka, S. Promotion of direct reprogramming by transformation-deficient Myc. Proc. Natl Acad. Sci. USA 107, 14152–14157 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Li, W. et al. Generation of human-induced pluripotent stem cells in the absence of exogenous Sox2. Stem Cells 27, 2992–3000 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Li, W. et al. Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors. Cell Stem Cell 4, 16–19 (2009).

    Article  PubMed  CAS  Google Scholar 

  47. Huangfu, D. et al. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nature Biotech. 26, 1269–1275 (2008).

    Article  CAS  Google Scholar 

  48. Zhu, S. et al. Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell Stem Cell 7, 651–655 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. Marion, R. M. et al. A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 460, 1149–1153 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Utikal, J. et al. Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature 460, 1145–1148 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hong, H. et al. Suppression of induced pluripotent stem cell generation by the p53-p21 pathway. Nature 460, 1132–1135 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Li, H. et al. The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 460, 1136–1139 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kawamura, T. et al. Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature 460, 1140–1144 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Menendez, S., Camus, S. & Belmonte, J. C. p53: guardian of reprogramming. Cell Cycle 9, 3887–3891 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. Marion, R. M. et al. Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells. Cell Stem Cell 4, 141–154 (2009).

    Article  CAS  PubMed  Google Scholar 

  56. Yehezkel, S. et al. Reprogramming of telomeric regions during the generation of human induced pluripotent stem cells and subsequent differentiation into fibroblast-like derivatives. Epigenetics 6, 63–75 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Vera, E., Canela, A., Fraga, M. F., Esteller, M. & Blasco, M. A. Epigenetic regulation of telomeres in human cancer. Oncogene 27, 6817–6833 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Doi, A. et al. Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nature Genet. 41, 1350–1353 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Aoi, T. et al. Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science 321, 699–702 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Stadtfeld, M., Nagaya, M., Utikal, J., Weir, G. & Hochedlinger, K. Induced pluripotent stem cells generated without viral integration. Science 322, 945–949 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Okita, K., Nakagawa, M., Hyenjong, H., Ichisaka, T. & Yamanaka, S. Generation of mouse induced pluripotent stem cells without viral vectors. Science 322, 949–953 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Kaji, K. et al. Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 458, 771–775 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Yu, J. et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science 324, 797–801 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Woltjen, K. et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458, 766–770 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Soldner, F. et al. Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136, 964–977 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhou, H. et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4, 381–384 (2009).

    Article  CAS  PubMed  Google Scholar 

  67. Kim, D. et al. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4, 472–476 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Warren, L. et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7, 618–630 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Mayshar, Y. et al. Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell 7, 521–531 (2010). First comprehensive study of chromosomal aberrations observed in HiPSCs in culture.

    Article  CAS  PubMed  Google Scholar 

  70. Draper, J. S., Moore, H. D., Ruban, L. N., Gokhale, P. J. & Andrews, P. W. Culture and characterization of human embryonic stem cells. Stem Cells Dev. 13, 325–336 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Maitra, A. et al. Genomic alterations in cultured human embryonic stem cells. Nature Genet. 37, 1099–1103 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Lefort, N. et al. Human embryonic stem cells reveal recurrent genomic instability at 20q11.21. Nature Biotech. 26, 1364–1366 (2008).

    Article  CAS  Google Scholar 

  73. Spits, C. et al. Recurrent chromosomal abnormalities in human embryonic stem cells. Nature Biotech. 26, 1361–1363 (2008).

    Article  CAS  Google Scholar 

  74. Inzunza, J. et al. Comparative genomic hybridization and karyotyping of human embryonic stem cells reveals the occurrence of an isodicentric X chromosome after long-term cultivation. Mol. Hum. Reprod. 10, 461–466 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Lefort, N., Perrier, A. L., Laabi, Y., Varela, C. & Peschanski, M. Human embryonic stem cells and genomic instability. Regen. Med. 4, 899–909 (2009). Recent review on the genomic instability of HESCs.

    Article  PubMed  Google Scholar 

  76. Narva, E. et al. High-resolution DNA analysis of human embryonic stem cell lines reveals culture-induced copy number changes and loss of heterozygosity. Nature Biotech. 28, 371–377 (2010).

    Article  CAS  Google Scholar 

  77. Gertow, K. et al. Trisomy 12 in HESC leads to no selective in vivo growth advantage in teratomas, but induces an increased abundance of renal development. J. Cell. Biochem. 100, 1518–1525 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Moon, S. H. et al. Effect of chromosome instability on the maintenance and differentiation of human embryonic stem cells in vitro and in vivo. Stem Cell Res. 6, 50–59 (2011).

    Article  CAS  PubMed  Google Scholar 

  79. Laurent, L. C. et al. Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell 8, 106–118 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Moriguchi, H., Chung, R. T. & Sato, C. Tumorigenicity of human induced pluripotent stem cells depends on the balance of gene expression between p21 and p53. Hepatology 51, 1088–1089 (2010).

    Article  PubMed  Google Scholar 

  81. Ben-David, U., Benvenisty, N. & Mayshar, Y. Genetic instability in human induced pluripotent stem cells: classification of causes and possible safeguards. Cell Cycle 9, 4603–4604 (2010).

    Article  CAS  PubMed  Google Scholar 

  82. Chin, M. H., Pellegrini, M., Plath, K. & Lowry, W. E. Molecular analyses of human induced pluripotent stem cells and embryonic stem cells. Cell Stem Cell 7, 263–269 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Guenther, M. G. et al. Chromatin structure and gene expression programs of human embryonic and induced pluripotent stem cells. Cell Stem Cell 7, 249–257 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Newman, A. M. & Cooper, J. B. Lab-specific gene expression signatures in pluripotent stem cells. Cell Stem Cell 7, 258–262 (2010).

    Article  CAS  PubMed  Google Scholar 

  85. Malchenko, S. et al. Cancer hallmarks in induced pluripotent cells: new insights. J. Cell. Physiol. 225, 390–393 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Ohm, J. E. et al. Cancer-related epigenome changes associated with reprogramming to induced pluripotent stem cells. Cancer Res. 70, 7662–7673 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hu, Q., Friedrich, A. M., Johnson, L. V. & Clegg, D. O. Memory in induced pluripotent stem cells: reprogrammed human retinal pigmented epithelial cells show tendency for spontaneous redifferentiation. Stem Cells 28, 1981–1991 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Ghosh, Z. et al. Persistent donor cell gene expression among human induced pluripotent stem cells contributes to differences with human embryonic stem cells. PLoS ONE 5, e8975 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Ron-Bigger, S. et al. Aberrant epigenetic silencing of tumor suppressor genes is reversed by direct reprogramming. Stem Cells 28, 1349–1354 (2010).

    Article  CAS  PubMed  Google Scholar 

  90. Jirtle, R. L. Genomic imprinting and cancer. Exp. Cell Res. 248, 18–24 (1999).

    Article  CAS  PubMed  Google Scholar 

  91. Lim, D. H. & Maher, E. R. Genomic imprinting syndromes and cancer. Adv. Genet. 70, 145–175 (2010).

    Article  CAS  PubMed  Google Scholar 

  92. Stadtfeld, M. et al. Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells. Nature 465, 175–181 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Rugg-Gunn, P. J., Ferguson-Smith, A. C. & Pedersen, R. A. Epigenetic status of human embryonic stem cells. Nature Genet. 37, 585–587 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Rugg-Gunn, P. J., Ferguson-Smith, A. C. & Pedersen, R. A. Status of genomic imprinting in human embryonic stem cells as revealed by a large cohort of independently derived and maintained lines. Hum. Mol. Genet. 16, R243–R251 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Adewumi, O. et al. Characterization of human embryonic stem cell lines by the International Stem CellInitiative. Nature Biotech. 25, 803–816 (2007).

    Article  CAS  Google Scholar 

  96. Frost, J. M. et al. The effects of culture on genomic imprinting profiles in human embryonic and fetal mesenchymal stem cells. Epigenetics 6, 52–62 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ghule, P. N. et al. Reprogramming the pluripotent cell cycle: restoration of an abbreviated G1 phase in human induced pluripotent stem (iPS) cells. J. Cell. Physiol. 13 Oct 2010 (doi:10.1002/jcp.22440).

  98. Singh, A. M. & Dalton, S. The cell cycle and Myc intersect with mechanisms that regulate pluripotency and reprogramming. Cell Stem Cell 5, 141–149 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Neganova, I., Zhang, X., Atkinson, S. & Lako, M. Expression and functional analysis of G1 to S. regulatory components reveals an important role for CDK2 in cell cycle regulation in human embryonic stem cells. Oncogene 28, 20–30 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Edel, M. J. et al. Rem2 GTPase maintains survival of human embryonic stem cells as well as enhancing reprogramming by regulating p53 and cyclin D1. Genes Dev. 24, 561–573 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Holubcova, Z. et al. Human embryonic stem cells suffer from centrosomal amplification. Stem Cells 29, 46–56 (2011).

    Article  CAS  PubMed  Google Scholar 

  102. Okita, K., Ichisaka, T. & Yamanaka, S. Generation of germline-competent induced pluripotent stem cells. Nature 448, 313–317 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Wernig, M., Meissner, A., Cassady, J. P. & Jaenisch, R. c-Myc is dispensable for direct reprogramming of mouse fibroblasts. Cell Stem Cell 2, 10–12 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Mali, P. et al. Improved efficiency and pace of generating induced pluripotent stem cells from human adult and fetal fibroblasts. Stem Cells 26, 1998–2005 (2008).

    Article  CAS  PubMed  Google Scholar 

  105. Miura, K. et al. Variation in the safety of induced pluripotent stem cell lines. Nature Biotech. 27, 743–745 (2009). First comparison of the tumorigenicity of mouse iPSCs from different somatic origins.

    Article  CAS  Google Scholar 

  106. Moriguchi, H., Chung, R. T. & Sato, C. An indicator for evaluating the risk of cancerous transformations of human induced pluripotent stem cells. Hepatology 51, 1085–1086 (2010).

    PubMed  Google Scholar 

  107. Gutierrez-Aranda, I. et al. Human induced pluripotent stem cells develop teratoma more efficiently and faster than human embryonic stem cells regardless the site of injection. Stem Cells 28, 1568–1570 (2010). Along with reference 86, this is one of the studies directly comparing the tumorigenicity of HESCs and HiPSCs.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Hentze, H., Graichen, R. & Colman, A. Cell therapy and the safety of embryonic stem cell-derived grafts. Trends Biotechnol. 25, 24–32 (2007).

    Article  CAS  PubMed  Google Scholar 

  109. Lee, A. S. et al. Effects of cell number on teratoma formation by human embryonic stem cells. Cell Cycle 8, 2608–2612 (2009).

    Article  CAS  PubMed  Google Scholar 

  110. Hentze, H. et al. Teratoma formation by human embryonic stem cells: evaluation of essential parameters for future safety studies. Stem Cell Res. 2, 198–210 (2009).

    Article  PubMed  Google Scholar 

  111. Eiges, R. et al. Establishment of human embryonic stem cell-transfected clones carrying a marker for undifferentiated cells. Curr. Biol. 11, 514–518 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. Choo, A. B. et al. Selection against undifferentiated human embryonic stem cells by a cytotoxic antibody recognizing podocalyxin-like protein-1. Stem Cells 26, 1454–1463 (2008).

    Article  CAS  PubMed  Google Scholar 

  113. Tan, H. L., Fong, W. J., Lee, E. H., Yap, M. & Choo, A. mAb 84, a cytotoxic antibody that kills undifferentiated human embryonic stem cells via oncosis. Stem Cells 27, 1792–1801 (2009).

    Article  CAS  PubMed  Google Scholar 

  114. Fong, C. Y., Peh, G. S., Gauthaman, K. & Bongso, A. Separation of SSEA-4 and TRA-1-60 labelled undifferentiated human embryonic stem cells from a heterogeneous cell population using magnetic-activated cell sorting (MACS) and fluorescence-activated cell sorting (FACS). Stem Cell Rev. 5, 72–80 (2009).

    Article  CAS  Google Scholar 

  115. Blum, B., Bar-Nur, O., Golan-Lev, T. & Benvenisty, N. The anti-apoptotic gene survivin contributes to teratoma formation by human embryonic stem cells. Nature Biotech. 27, 281–287 (2009).

    Article  CAS  Google Scholar 

  116. Smith, K. N., Singh, A. M. & Dalton, S. Myc represses primitive endoderm differentiation in pluripotent stem cells. Cell Stem Cell 7, 343–354 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Varlakhanova, N. V. et al. myc maintains embryonic stem cell pluripotency and self-renewal. Differentiation 80, 9–19 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Smith, K. & Dalton, S. Myc transcription factors: key regulators behind establishment and maintenance of pluripotency. Regen. Med. 5, 947–959 (2010).

    Article  CAS  PubMed  Google Scholar 

  119. Kim, J. et al. A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell 143, 313–324 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Schuldiner, M., Itskovitz-Eldor, J. & Benvenisty, N. Selective ablation of human embryonic stem cells expressing a “suicide” gene. Stem Cells 21, 257–265 (2003).

    Article  CAS  PubMed  Google Scholar 

  121. Krishna, K. A., Rao, G. V. & Rao, K. S. Stem cell-based therapy for the treatment of Type 1 diabetes mellitus. Regen. Med. 2, 171–177 (2007).

    Article  CAS  PubMed  Google Scholar 

  122. Korsgren, O. & Nilsson, B. Improving islet transplantation: a road map for a widespread application for the cure of persons with type I diabetes. Curr. Opin. Organ Transplant. 14, 683–687 (2009).

    Article  PubMed  Google Scholar 

  123. Dean, S. K., Yulyana, Y., Williams, G., Sidhu, K. S. & Tuch, B. E. Differentiation of encapsulated embryonic stem cells after transplantation. Transplantation 82, 1175–1184 (2006).

    Article  PubMed  Google Scholar 

  124. Giorgetti, A. et al. Generation of induced pluripotent stem cells from human cord blood using OCT4 and SOX2. Cell Stem Cell 5, 353–357 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Kim, J. B. et al. Direct reprogramming of human neural stem cells by OCT4. Nature 461, 649–653 (2009).

    Article  CAS  PubMed  Google Scholar 

  126. Russo, E. Follow the money—the politics of embryonic stem cell research. PLoS Biol. 3, e234 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Hussein, S.M et al. Copy number variation and selection during reprogramming to pluripotency. Nature 471, 58–62 (2011).

    Article  CAS  PubMed  Google Scholar 

  128. Gore, A. et al. Somatic coding mutations in human induced pluripotent stem cells. Nature 471, 63–67 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Lister, R. et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471, 68–73 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Studies by the authors, described in this Review, have been partially supported by funds from the Morasha-ISF (Grant No. 943/09) and Center of Excellence: The Legacy Heritage Fund Program of The Israel Science Foundation (Grant No. 1801/10). The authors would like to thank E. Meshorer and D. Ronen for critically reading the manuscript, and T. Golan-Lev for her assistance with the figures.

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  1. nissimb@cc.huji.ac.il

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  1. Department of Genetics, Stem Cell Unit, Silberman Institute of Life Sciences, The Hebrew University, 91904, Jerusalem, Israel

    Uri Ben-David & Nissim Benvenisty

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  1. Uri Ben-David
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Glossary

Teratoma

Benign tumour that is composed of differentiated tissues from all three germ layers.

Teratocarcinoma

Tumour composed of a mixture of differentiated tissues of the three germ layers. Contains foci of completely undifferentiated cells, called embryonal carcinoma cells, and is highly malignant.

Genomic imprinting

The expression of specific genes from either the maternal or the paternal allele.

CpG island shore

DNA sequence that flanks CpG islands.

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Ben-David, U., Benvenisty, N. The tumorigenicity of human embryonic and induced pluripotent stem cells. Nat Rev Cancer 11, 268–277 (2011). https://doi.org/10.1038/nrc3034

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