Deconstructing Stem Cell Tumorigenicity: A Roadmap to Safe Regenerative Medicine

Abstract

Many of the earliest stem cell studies were conducted on cells isolated from tumors rather than from embryos. Of particular interest was research on embryonic carcinoma cells (EC), a type of stem cell derived from teratocarcinoma. The EC research laid the foundation for the later discovery of and subsequent work on embryonic stem cells (ESC). Both ESC isolated from the mouse (mESC) and then later from humans (hESC) shared not only pluripotency with their EC cousins, but also robust tumorigenicity as each readily form teratoma. Surprisingly, decades after the discovery of mESC, the question of what drives ESC to form tumors remains largely an open one. This gap in the field is particularly serious as stem cell tumorigenicity represents the key obstacle to the safe use of stem cell-based regenerative medicine therapies. Although some adult stem cell therapies appear to be safe, they have only a very narrow range of uses in human disease. Our understanding of the tumorigenicity of human induced pluripotent stem cells (IPSC), perhaps the most promising modality for future patient-specific regenerative medicine therapies, is rudimentary. However, IPSC are predicted to possess tumorigenic potential equal to or greater than that of ESC. Here, the links between pluripotency and tumorigenicity are explored. New methods for more accurately testing the tumorigenic potential of IPSC and of other stem cells applicable to regenerative medicine are proposed. Finally, the most promising emerging approaches for overcoming the challenges of stem cell tumorigenicity are highlighted. Disclosure of potential conflicts of interest is found at the end of this article.

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References 47

1. 1.

   Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292:154-156.

   Not in our library10.1038/292154a0

2. 2.

   Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA. 1981;78:7634-7638.

   Not in our library10.1073/pnas.78.12.7634

3. 3.

   Doetschman TC, Eistetter H, Katz M, et al. The in vitro development of blastocyst-derived embryonic stem cell lines: Formation of visceral yolk sac, blood islands and myocardium. J Embryol Exp Morphol. 1985;87:27-45.

   Not in our library

4. 4.

   Solter D. From teratocarcinomas to embryonic stem cells and beyond: A history of embryonic stem cell research. Nat Rev Genet. 2006;7:319-327.

   Not in our library10.1038/nrg1827

5. 5.

   Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature. 2007;448:313-317.

   Not in our library10.1038/nature05934

6. 6.

   Shih CC, Forman SJ, Chu P, et al. Human embryonic stem cells are prone to generate primitive, undifferentiated tumors in engrafted human fetal tissues in severe combined immunodeficient mice. Stem Cells Dev. 2007;16:893-902.

   Not in our library10.1089/scd.2007.0070

7. 7.

   Sperger JM, Chen X, Draper JS, et al. Gene expression patterns in human embryonic stem cells and human pluripotent germ cell tumors. Proc Natl Acad Sci USA. 2003;100:13350-13355.

   Not in our library10.1073/pnas.2235735100

8. 8.

   Wong DJ, Liu H, Ridky TW, et al. Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell Stem Cell. 2008;2:333-344.

   Not in our library10.1016/j.stem.2008.02.009

9. 9.

   Chiou SH, Yu CC, Huang CY, et al. Positive correlations of Oct-4 and Nanog in oral cancer stem-like cells and high-grade oral squamous cell carcinoma. Clin Cancer Res. 2008;14:4085-4095.

   Not in our library10.1158/1078-0432.ccr-07-4404

10. 10.

    Ben-Porath I, Thomson MW, Carey VJ, et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet. 2008;40:499-507.

    Not in our library10.1038/ng.127

11. 11.

    Yamanaka S. Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell. 2007;1:39-49.

    Not in our library10.1016/j.stem.2007.05.012

12. 12.

    Knoepfler PS. Why myc? An unexpected ingredient in the stem cell cocktail. Cell Stem Cell. 2008;2:18-21.

    Not in our library10.1016/j.stem.2007.12.004

13. 13.

    Wei D, Kanai M, Huang S, et al. Emerging role of KLF4 in human gastrointestinal cancer. Carcinogenesis. 2006;27:23-31.

    Not in our library10.1093/carcin/bgi243

14. 14.

    Chen Y, Shi L, Zhang L, et al. The molecular mechanism governing the oncogenic potential of SOX2 in breast cancer. J Biol Chem. 2008;283:17969-17978.

    Not in our library10.1074/jbc.m802917200

15. 15.

    Palma I, Pena RY, Contreras A, et al. Participation of OCT3/4 and beta-catenin during dysgenetic gonadal malignant transformation. Cancer Lett. 2008;263:204-211.

    Not in our library10.1016/j.canlet.2008.01.019

16. 16.

    Eilers M, Eisenman RN. Myc's broad reach. Genes Dev. 2008;22:2755-2766.

    Not in our library10.1101/gad.1712408

17. 17.

    Knoepfler PS, Cheng PF, Eisenman RN. N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation. Genes Dev. 2002;16:2699-2712.

    Not in our library10.1101/gad.1021202

18. 18.

    Wilson A, Murphy MJ, Oskarsson T, et al. c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev. 2004;18:2747-2763.

    Not in our library10.1101/gad.313104

19. 19.

    Cartwright P, McLean C, Sheppard A, et al. LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism. Development. 2005;132:885-896.

    Not in our library10.1242/dev.01670

20. 20.

    Nakagawa M, Koyanagi M, Tanabe K, et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol. 2008;26:101-106.

    Not in our library10.1038/nbt1374

21. 21.

    Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917-1920.

    Not in our library10.1126/science.1151526

22. 22.

    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663-676.

    Not in our library10.1016/j.cell.2006.07.024

23. 23.

    Jiang J, Chan YS, Loh YH, et al. A core Klf circuitry regulates self-renewal of embryonic stem cells. Nat Cell Biol. 2008;10:353-360.

    Not in our library10.1038/ncb1698

24. 24.

    Ben-Hur T, Idelson M, Khaner H, et al. Transplantation of human embryonic stem cell-derived neural progenitors improves behavioral deficit in Parkinsonian rats. Stem Cells. 2004;22:1246-1255.

    Not in our library10.1634/stemcells.2004-0094

25. 25.

    Fujikawa T, Oh SH, Pi L, et al. Teratoma formation leads to failure of treatment for type I diabetes using embryonic stem cell-derived insulin-producing cells. Am J Pathol. 2005;166:1781-1791.

    Not in our library10.1016/s0002-9440(10)62488-1

26. 26.

    Ito M, Kobayashi K, Nakahata T. NOD/Shi-scid IL2rgamma(null) (NOG) mice more appropriate for humanized mouse models. Curr Top Microbiol Immunol. 2008;324:53-76.

    Not in our library10.1007/978-3-540-75647-7_3

27. 27.

    Land H, Parada LF, Weinberg RA. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature. 1983;304:596-601.

    Not in our library10.1038/304596a0

28. 28.

    Yancopoulos GD, Nisen PD, Tesfaye A, et al. N-myc can cooperate with ras to transform normal cells in culture. Proc Natl Acad Sci USA. 1985;82:5455-5459.

    Not in our library10.1073/pnas.82.16.5455

29. 29.

    Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature. 2007;448:313-317.

    Not in our library10.1038/nature05934

30. 30.

    Shi Y, Do JT, Desponts C, et al. A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell. 2008;2:525-528.

    Not in our library10.1016/j.stem.2008.05.011

31. 31.

    Huangfu D, Maehr R, Guo W, et al. Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol. 2008;26:795-797.

    Not in our library10.1038/nbt1418

32. 32.

    Wernig M, Meissner A, Jaenisch R. C-Myc is dispensable for direct reprogramming of mouse fibroblasts. Cell Stem Cell. 2008;2:10-12.

    Not in our library10.1016/j.stem.2007.12.001

33. 33.

    Baker DE, Harrison NJ, Maltby E, et al. Adaptation to culture of human embryonic stem cells and oncogenesis in vivo. Nat Biotechnol. 2007;25:207-215.

    Not in our library10.1038/nbt1285

34. 34.

    Maitra A, Arking DE, Shivapurkar N, et al. Genomic alterations in cultured human embryonic stem cells. Nat Genet. 2005;37:1099-1103.

    Not in our library10.1038/ng1631

35. 35.

    Bauer G, Dao MA, Case SS, et al. In vivo biosafety model to assess the risk of adverse events from retroviral and lentiviral vectors. Mol Ther. 2008;16:1308-1315.

    Not in our library10.1038/mt.2008.93

36. 36.

    Giordano A, Galderisi U, Marino IR. From the laboratory bench to the patient's bedside: An update on clinical trials with mesenchymal stem cells. J Cell Physiol. 2007;211:27-35.

    Not in our library10.1002/jcp.20959

37. 37.

    Werbowetski-Ogilvie TE, Bosse M, Stewart M, et al. Characterization of human embryonic stem cells with features of neoplastic progression. Nat Biotechnol. 2009;27:91-97.

    Not in our library10.1038/nbt.1516

38. 38.

    Bernstein BE, Mikkelsen TS, Xie X, et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006;125:315-326.

    Not in our library10.1016/j.cell.2006.02.041

39. 39.

    Allegrucci C, Wu YZ, Thurston A, et al. Restriction landmark genome scanning identifies culture-induced DNA methylation instability in the human embryonic stem cell epigenome. Hum Mol Genet. 2007;16:1253-1268.

    Not in our library10.1093/hmg/ddm074

40. 40.

    Humpherys D, Eggan K, Akutsu H, et al. Epigenetic instability in ES cells and cloned mice. Science. 2001;293:95-97.

    Not in our library10.1126/science.1061402

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