Teratomas derived from human embryonic stem (hES) cells are unique among oncogenic phenomena as they are polyclonal and develop from apparently normal cells. 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.
Bibliographical noteFunding Information:
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.