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The anti-apoptotic gene survivin contributes to teratoma formation by human embryonic stem cells

Abstract

Teratomas derived from human embryonic stem (hES) cells are unique among oncogenic phenomena as they are polyclonal and develop from apparently normal cells1,2. A deeper understanding of this process should aid in the development of safer cell therapies and may help elucidate the basic principles of tumor initiation. We find that transplantation of diploid hES cells from four independent cell lines generates benign teratomas with no sign of malignancy or persisting embryonal carcinoma-like cells. In contrast, mouse embryonic stem (mES) cells from four cell lines consistently generate malignant teratocarcinomas. Global gene expression analysis shows that survivin (BIRC5), an anti-apoptotic oncofetal gene, is highly expressed in hES cells and teratomas but not in embryoid bodies. Genetic and pharmacological ablation of survivin induces apoptosis in hES cells and in teratomas both in vitro and in vivo. We suggest that continued expression of survivin upon differentiation in vivo may contribute to teratoma formation by hES cells.

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Figure 1: HES cells induce teratomas that are smaller than mES-cell tumors, do not contain EC-like cells, are karyotypically normal and are nonaggressive.
Figure 2: DNA microarray analysis to identify genes expressed in hES cells and teratomas but not mature embryoid bodies.
Figure 3: Survivin is highly expressed in hES cells and teratomas.
Figure 4: Genetic and pharmacological interruption of survivin activity induces apoptosis in hES cells and teratomas in vitro and in vivo.

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References

  1. Blum, B. & Benvenisty, N. Clonal analysis of human embryonic stem cell differentiation into teratomas. Stem Cells 25, 1924–1930 (2007).

    Article  CAS  Google Scholar 

  2. Blum, B. & Benvenisty, N. The tumorigenicity of human embryonic stem cells. Adv. Cancer Res. 100, 133–158 (2008).

    Article  Google Scholar 

  3. Gidekel, S., Pizov, G., Bergman, Y. & Pikarsky, E. Oct-3/4 is a dose-dependent oncogenic fate determinant. Cancer Cell 4, 361–370 (2003).

    Article  CAS  Google Scholar 

  4. Oosterhuis, J.W. & Looijenga, L.H. Testicular germ-cell tumours in a broader perspective. Nat. Rev. Cancer 5, 210–222 (2005).

    Article  CAS  Google Scholar 

  5. Baker, D.E. et al. Adaptation to culture of human embryonic stem cells and oncogenesis in vivo. Nat. Biotechnol. 25, 207–215 (2007).

    Article  CAS  Google Scholar 

  6. Cowan, C.A. et al. Derivation of embryonic stem-cell lines from human blastocysts. N. Engl. J. Med. 350, 1353–1356 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Looijenga, L.H. et al. POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors. Cancer Res. 63, 2244–2250 (2003).

    CAS  PubMed  Google Scholar 

  9. Hart, A.H. et al. The pluripotency homeobox gene NANOG is expressed in human germ cell tumors. Cancer 104, 2092–2098 (2005).

    Article  CAS  Google Scholar 

  10. Martin, G.R. & Evans, M.J. The morphology and growth of a pluripotent teratocarcinoma cell line and its derivatives in tissue culture. Cell 2, 163–172 (1974).

    Article  CAS  Google Scholar 

  11. Damjanov, I. & Andrews, P.W. Ultrastructural differentiation of a clonal human embryonal carcinoma cell line in vitro. Cancer Res. 43, 2190–2198 (1983).

    CAS  PubMed  Google Scholar 

  12. Albanell, J. et al. Telomerase activity in germ cell cancers and mature teratomas. J. Natl. Cancer Inst. 91, 1321–1326 (1999).

    Article  CAS  Google Scholar 

  13. Lowe, S.W., Jacks, T., Housman, D.E. & Ruley, H.E. Abrogation of oncogene-associated apoptosis allows transformation of p53-deficient cells. Proc. Natl. Acad. Sci. USA 91, 2026–2030 (1994).

    Article  CAS  Google Scholar 

  14. Itskovitz-Eldor, J. et al. Differentiation of human embryonic stem cells into embryoid bodies compromising the three embryonic germ layers. Mol. Med. 6, 88–95 (2000).

    Article  CAS  Google Scholar 

  15. Diehn, M. et al. SOURCE: a unified genomic resource of functional annotations, ontologies, and gene expression data. Nucleic Acids Res. 31, 219–223 (2003).

    Article  CAS  Google Scholar 

  16. Li, F. et al. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 396, 580–584 (1998).

    Article  CAS  Google Scholar 

  17. Ambrosini, G., Adida, C. & Altieri, D.C. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat. Med. 3, 917–921 (1997).

    Article  CAS  Google Scholar 

  18. Adida, C. et al. Developmentally regulated expression of the novel cancer anti-apoptosis gene survivin in human and mouse differentiation. Am. J. Pathol. 152, 43–49 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Uren, A.G. et al. Survivin and the inner centromere protein INCENP show similar cell-cycle localization and gene knockout phenotype. Curr. Biol. 10, 1319–1328 (2000).

    Article  CAS  Google Scholar 

  20. Grossman, D., Kim, P.J., Schechner, J.S. & Altieri, D.C. Inhibition of melanoma tumor growth in vivo by survivin targeting. Proc. Natl. Acad. Sci. USA 98, 635–640 (2001).

    Article  CAS  Google Scholar 

  21. O'Connor, D.S., Wall, N.R., Porter, A.C. & Altieri, D.C. A p34(cdc2) survival checkpoint in cancer. Cancer Cell 2, 43–54 (2002).

    Article  CAS  Google Scholar 

  22. Mesri, M., Wall, N.R., Li, J., Kim, R.W. & Altieri, D.C. Cancer gene therapy using a survivin mutant adenovirus. J. Clin. Invest. 108, 981–990 (2001).

    Article  CAS  Google Scholar 

  23. Ma, X. et al. High-level expression, purification and pro-apoptosis activity of HIV-TAT-survivin (T34A) mutant to cancer cells in vitro. J. Biotechnol. 123, 367–378 (2006).

    Article  CAS  Google Scholar 

  24. Walt, H., Oosterhuis, J.W. & Stevens, L.C. Experimental testicular germ cell tumorigenesis in mouse strains with and without spontaneous tumours differs from development of germ cell tumours of the adult human testis. Int. J. Androl. 16, 267–271 (1993).

    Article  CAS  Google Scholar 

  25. Takahashi, K., Mitsui, K. & Yamanaka, S. Role of ERas in promoting tumour-like properties in mouse embryonic stem cells. Nature 423, 541–545 (2003).

    Article  CAS  Google Scholar 

  26. Kameda, T. & Thomson, J.A. Human ERas gene has an upstream premature polyadenylation signal that results in a truncated, noncoding transcript. Stem Cells 23, 1535–1540 (2005).

    Article  CAS  Google Scholar 

  27. Rangarajan, A., Hong, S.J., Gifford, A. & Weinberg, R.A. Species- and cell type-specific requirements for cellular transformation. Cancer Cell 6, 171–183 (2004).

    Article  CAS  Google Scholar 

  28. Damjanov, I. & Andrews, P.W. The terminology of teratocarcinomas and teratomas. Nat. Biotechnol. 25, 1212 (2007).

    Article  CAS  Google Scholar 

  29. Lensch, M.W. & Ince, T.A. The terminology of teratocarcinomas and teratomas. Nat. Biotechnol. 25, 1211 (2007).

    Article  CAS  Google Scholar 

  30. Yang, D., Welm, A. & Bishop, J.M. Cell division and cell survival in the absence of survivin. Proc. Natl. Acad. Sci. USA 101, 15100–15105 (2004).

    Article  CAS  Google Scholar 

  31. Goga, A., Yang, D., Tward, A.D., Morgan, D.O. & Bishop, J.M. Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC. Nat. Med. 13, 820–827 (2007).

    Article  CAS  Google Scholar 

  32. 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  Google Scholar 

  33. 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  Google Scholar 

  34. Altieri, D.C. Survivin, cancer networks and pathway-directed drug discovery. Nat. Rev. Cancer 8, 61–70 (2008).

    Article  CAS  Google Scholar 

  35. Dvash, T. et al. Temporal gene expression during differentiation of human embryonic stem cells and embryoid bodies. Hum. Reprod. 19, 2875–2883 (2004).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Douglas Grossman (University of Utah) and Dario C. Altieri (University of Massachusetts) for survivin-GFP expression vectors; Austin Smith (University of Cambridge, UK) for Nanog antibody; Yehudit Bergman (Hebrew University of Jerusalem) for Oct4 antibody; Eran Meshorer (Hebrew University of Jerusalem) for J1, R1 and E14 mES cells; Amir Eden (Hebrew University of Jerusalem) for the P53−/− Ras and E1A transformed MEFs; Yoav Sherman and Victoria Doviner for assistance with tumor histology; Yehuda Tzfati and Noa Lam for help with telomerase activity assays; Micha Drukker for help with establishing the teratoma production protocol; Yoav Mayshar and Ofra Yanuka for assistance with DNA microarray analysis; Marjorie Pick for help with flow cytometry experiments; and Nadav Sharon for help with statistical analyses. This research was partially supported by funds from Bereshit Consortium, The Israeli Ministry of Trade and Industry (Grant number 37675), the European Community (ESTOOLS, Grant number 018739) and by the Legacy Heritage Fund.

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Contributions

B.B. and N.B. conceived and designed experiments. B.B. performed all experiments and data analyses. O.B.-N. assisted in OCT4 and Nanog Immunofluorescence on undifferentiated mES. T.G.-L. assisted in karyotypyng analyses. B.B. and N.B. wrote the manuscript.

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Correspondence to Nissim Benvenisty.

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Blum, B., Bar-Nur, O., Golan-Lev, T. et al. The anti-apoptotic gene survivin contributes to teratoma formation by human embryonic stem cells. Nat Biotechnol 27, 281–287 (2009). https://doi.org/10.1038/nbt.1527

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