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Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies

Abstract

Human pluripotent stem cells (PSCs) are a leading candidate for cell-based therapies because of their capacity for unlimited self renewal and pluripotent differentiation. These advances have recently culminated in the first-in-human PSC clinical trials by Geron, Advanced Cell Technology and the Kobe Center for Developmental Biology for the treatment of spinal cord injury and macular degeneration. Despite their therapeutic promise, a crucial hurdle for the clinical implementation of human PSCs is their potential to form tumors in vivo. In this Perspective, we present an overview of the mechanisms underlying the tumorigenic risk of human PSC–based therapies and discuss current advances in addressing these challenges.

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Figure 1: Tumorigenic hurdles to clinical translation of PSC-based therapies.
Figure 2: Potential mechanisms for tumorigenicity during the induction of pluripotency in somatic cells.

References

  1. Ben-David, U. & Benvenisty, N. The tumorigenicity of human embryonic and induced pluripotent stem cells. Nat. Rev. Cancer 11, 268–277 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. DeFrancesco, L. Fits and starts for Geron. Nat. Biotechnol. 27, 877 (2009).

    Article  CAS  Google Scholar 

  3. 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 

  4. Roy, N.S. et al. Functional engraftment of human ES cell–derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat. Med. 12, 1259–1268 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Kriks, S. et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature 480, 547–551 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cui, L. et al. WNT signaling determines tumorigenicity and function of ESC-derived retinal progenitors. J. Clin. Invest. 123, 1647–1661 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Doi, D. et al. Prolonged maturation culture favors a reduction in the tumorigenicity and the dopaminergic function of human ESC-derived neural cells in a primate model of Parkinson's disease. Stem Cells 30, 935–945 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Amariglio, N. et al. Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med. 6, e1000029 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Cyranoski, D. Strange lesions after stem-cell therapy. Nature 465, 997 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Strauss, S. Geron trial resumes, but standards for stem cell trials remain elusive. Nat. Biotechnol. 28, 989–990 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Schwartz, S.D. et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet 379, 713–720 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Cyranoski, D. Stem cells cruise to clinic. Nature 494, 413 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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 

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

    Article  PubMed  CAS  Google Scholar 

  16. Meyer, N. & Penn, L.Z. Reflecting on 25 years with MYC. Nat. Rev. Cancer 8, 976–990 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. Markoulaki, S. et al. Transgenic mice with defined combinations of drug-inducible reprogramming factors. Nat. Biotechnol. 27, 169–171 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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 

  20. Lin, C.Y. et al. Transcriptional amplification in tumor cells with elevated c-Myc. Cell 151, 56–67 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hochedlinger, K., Yamada, Y., Beard, C. & Jaenisch, R. Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell 121, 465–477 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Lee, T.K., Cheung, V.C. & Ng, I.O. Liver tumor-initiating cells as a therapeutic target for hepatocellular carcinoma. Cancer Lett. published online http://dx.doi.org/10.1016/j.canlet.2012.05.001 (28 May 2012).

  23. Bass, A.J. et al. SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat. Genet. 41, 1238–1242 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rowland, B.D., Bernards, R. & Peeper, D.S. The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene. Nat. Cell Biol. 7, 1074–1082 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Mikkelsen, T.S. et al. Dissecting direct reprogramming through integrative genomic analysis. Nature 454, 49–55 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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 

  27. 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 

  28. 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 

  29. 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 

  30. Jia, F. et al. A nonviral minicircle vector for deriving human iPS cells. Nat. Methods 7, 197–199 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ban, H. et al. Efficient generation of transgene-free human induced pluripotent stem cells (iPSCs) by temperature-sensitive Sendai virus vectors. Proc. Natl. Acad. Sci. USA 108, 14234–14239 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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 

  33. Lee, J. et al. Activation of innate immunity is required for efficient nuclear reprogramming. Cell 151, 547–558 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Miyoshi, N. et al. Reprogramming of mouse and human cells to pluripotency using mature microRNAs. Cell Stem Cell 8, 633–638 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. 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 

  36. Desponts, C. & Ding, S. Using small molecules to improve generation of induced pluripotent stem cells from somatic cells. Methods Mol. Biol. 636, 207–218 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. 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 

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

    Article  CAS  PubMed  Google Scholar 

  39. 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 

  40. Harris, W.J. et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell 21, 473–487 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. Gaudet, F. et al. Induction of tumors in mice by genomic hypomethylation. Science 300, 489–492 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Wollert, K.C. et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 364, 141–148 (2004).

    Article  PubMed  Google Scholar 

  43. Vanneste, E. et al. Chromosome instability is common in human cleavage-stage embryos. Nat. Med. 15, 577–583 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Hyka-Nouspikel, N. et al. Deficient DNA damage response and cell cycle checkpoints lead to accumulation of point mutations in human embryonic stem cells. Stem Cells 30, 1901–1910 (2012).

    Article  CAS  PubMed  Google Scholar 

  45. Desmarais, J.A. et al. Human embryonic stem cells fail to activate CHK1 and commit to apoptosis in response to DNA replication stress. Stem Cells 30, 1385–1393 (2012).

    Article  CAS  PubMed  Google Scholar 

  46. Mayshar, Y. et al. Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell 7, 521–531 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Draper, J.S. et al. Recurrent gain of chromosomes 17q and 12 in cultured human embryonic stem cells. Nat. Biotechnol. 22, 53–54 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  49. Spits, C. et al. Recurrent chromosomal abnormalities in human embryonic stem cells. Nat. Biotechnol. 26, 1361–1363 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Amps, K. et al. Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage. Nat. Biotechnol. 29, 1132–1144 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. Werbowetski-Ogilvie, T.E. et al. Characterization of human embryonic stem cells with features of neoplastic progression. Nat. Biotechnol. 27, 91–97 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. 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 

  53. Narsinh, K.H. et al. Single cell transcriptional profiling reveals heterogeneity of human induced pluripotent stem cells. J. Clin. Invest. 121, 1217–1221 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Pearl, J.I., Kean, L.S., Davis, M.M. & Wu, J.C. Pluripotent stem cells: immune to the immune system? Sci. Transl. Med. 4, 164ps125 (2012).

    Article  CAS  Google Scholar 

  55. de Almeida, P.E., Ransohoff, J.D., Nahid, A. & Wu, J.C. Immunogenicity of pluripotent stem cells and their derivatives. Circ. Res. 112, 549–561 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zhao, T., Zhang, Z.N., Rong, Z. & Xu, Y. Immunogenicity of induced pluripotent stem cells. Nature 474, 212–215 (2011).

    Article  CAS  PubMed  Google Scholar 

  57. Araki, R. et al. Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells. Nature 494, 100–104 (2013).

    Article  CAS  PubMed  Google Scholar 

  58. Guha, P., Morgan, J.W., Mostoslavsky, G., Rodrigues, N.P. & Boyd, A.S. Lack of immune response to differentiated cells derived from syngeneic induced pluripotent stem cells. Cell Stem Cell 12, 407–412 (2013).

    Article  CAS  PubMed  Google Scholar 

  59. Drukker, M. et al. Characterization of the expression of MHC proteins in human embryonic stem cells. Proc. Natl. Acad. Sci. USA 99, 9864–9869 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Rideout, W.M. III, Hochedlinger, K., Kyba, M., Daley, G.Q. & Jaenisch, R. Correction of a genetic defect by nuclear transplantation and combined cell and gene therapy. Cell 109, 17–27 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Pearl, J.I. et al. Short-term immunosuppression promotes engraftment of embryonic and induced pluripotent stem cells. Cell Stem Cell 8, 309–317 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Swijnenburg, R.J. et al. Immunosuppressive therapy mitigates immunological rejection of human embryonic stem cell xenografts. Proc. Natl. Acad. Sci. USA 105, 12991–12996 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Schwartz, S.D. et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet 379, 713–720 (2012).

    Article  CAS  PubMed  Google Scholar 

  64. 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 

  65. Tang, C. et al. An antibody against SSEA-5 glycan on human pluripotent stem cells enables removal of teratoma-forming cells. Nat. Biotechnol. 29, 829–834 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Dubois, N.C. et al. SIRPA is a specific cell-surface marker for isolating cardiomyocytes derived from human pluripotent stem cells. Nat. Biotechnol. 29, 1011–1018 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ben-David, U. et al. Selective elimination of human pluripotent stem cells by an oleate synthesis inhibitor discovered in a high-throughput screen. Cell Stem Cell 12, 167–179 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Peckham, M.J., McElwain, T.J., Barrett, A. & Hendry, W.F. Combined management of malignant teratoma of the testis. Lancet 314, 267–270 (1979).

    Article  Google Scholar 

  69. Di Stasi, A. et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365, 1673–1683 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank A. Morris and J. Wha-Rhee for preparing the illustrations. Because of space constraints, we were unable to include all relevant studies regarding the tumorigenicity of pluripotent stem cells; we apologize to those investigators whose valuable work we have omitted. This work was supported in part by US National Institutes of Health grants HL093172, HL099117 and EB009689, the Burroughs Wellcome Fund Career Award in the Biomedical Sciences, American Heart Association grant EIA14420025 and California Institute of Regenerative Medicine (CIRM) grants DR2-05394 and TR3-05556 (J.C.W.); CIRM Tools & Technology II (I.L.W.); a Bio-X graduate student fellowship (A.S.L.); and Howard Hughes Medical Institute research training fellowships (A.S.L. and C.T.).

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Correspondence to Mahendra S Rao, Irving L Weissman or Joseph C Wu.

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Lee, A., Tang, C., Rao, M. et al. Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies. Nat Med 19, 998–1004 (2013). https://doi.org/10.1038/nm.3267

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