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Characterization of human embryonic stem cells with features of neoplastic progression

Nature Biotechnology volume 27, pages 91–97 (2009)Cite this article

Abstract

Cultured human embryonic stem (hES) cells can acquire genetic and epigenetic changes that make them vulnerable to transformation. As hES cells with cancer-cell characteristics share properties with normal hES cells, such as self-renewal, teratoma formation and the expression of pluripotency markers, they may be misconstrued as superior hES cells with enhanced 'stemness'. We characterize two variant hES cell lines (v-hESC-1 and v-hESC-2) that express pluripotency markers at high levels and do not harbor chromosomal abnormalities by standard cytogenetic measures. We show that the two lines possess some features of neoplastic progression, including a high proliferative capacity, growth-factor independence, a 9- to 20-fold increase in frequency of tumor-initiating cells, niche independence and aberrant lineage specification, although they are not malignant. Array comparative genomic hybridization reveals an amplification at 20q11.1-11.2 in v-hESC-1 and a deletion at 5q34a-5q34b;5q3 and a mosaic gain of chromosome 12 in v-hESC-2. These results emphasize the need for functional characterization to distinguish partially transformed and normal hES cells.

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Figure 1: Variant hES cells are morphologically and phenotypically different from normal hES cells.
Figure 2: Variant hES cells exhibit dysregulated cell-cycle and self-renewal properties in vitro and tumor-initiating cell frequency in vivo.
Figure 3: v-hESC-1 cells have acquired FGFR1 and IGF1R expression on all pluripotent cells within the culture and are refractory to differentiation in vitro.
Figure 4: Neural progeny of variant hES cells retain molecular and functional abnormalities of their parent cells.

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Acknowledgements

This work was funded by the Canadian Institute of Health Research, the National Cancer Institute of Canada (NCIC), Ontario Institute of Cancer Research (OICR) and the Canadian Cancer Society (CCS). A fellowship from the NCIC supports T.E.W.-O. and support to M.B. from the Canada Research Chair Program. In addition, thanks to Jiabi Yang for technical support in scoring teratoma formation assays and members of the Stem Cell and Cancer Research Institute for helpful insights during the writing of the manuscript.

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Authors and Affiliations

  1. Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, MDCL 5029, McMaster University, 1200 Main Street West, Hamilton, L8N 3Z5, Ontario, Canada

    Tamra E Werbowetski-Ogilvie, Marc Bossé, Morag Stewart, Angelique Schnerch, Veronica Ramos-Mejia, Anne Rouleau, Tracy Wynder, Christopher Wynder & Mickie Bhatia

  2. Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, McMaster University, Hamilton, L8N 3Z5, Ontario, Canada

    Mary-Jo Smith

  3. Department of Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, L8S 4M1, Ontario, Canada

    Steve Dingwall, Tim Carter & Doug Boreham

  4. PerkinElmer Life and Analytical Sciences, 940 Winter Street, Waltham, 02451, Masschusetts, USA

    Christopher Williams & Charles Harris

  5. Department of Pathology and Molecular Medicine, Credit Valley Hospital, 2200 Eglinton Avenue West, Mississauga, L5M 2N1, Ontario, Canada

    Joanna Dolling

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Contributions

T.E.W.-O. performed and designed experiments, analyzed data and assisted in writing the manuscript. M.B., M.S., V.R.-M., A.R., T.W., S.D., T.C., C.W. (from PerkinElmer) and C.H. performed experiments. A.S. analyzed bioinformatics data, and M.-J.S. conducted histological analysis. J.D., C.W. (from McMaster) and D.B. were collaborators on the paper. M.B. designed experiments, interpreted and assisted in writing the manuscript.

Corresponding author

Correspondence to Mickie Bhatia.

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Werbowetski-Ogilvie, T., Bossé, M., Stewart, M. et al. Characterization of human embryonic stem cells with features of neoplastic progression. Nat Biotechnol 27, 91–97 (2009). https://doi.org/10.1038/nbt.1516

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