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In vitro generation of human cells with cancer stem cell properties

Nature Cell Biology volume 13, pages 1051–1061 (2011)Cite this article

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Abstract

Cancer stem cells (CSCs) have been implicated in the maintenance and progression of several types of cancer. The origin and cellular properties of human CSCs are poorly characterized. Here we show that CSC-like cells can be generated in vitro by oncogenic reprogramming of human somatic cells during neoplastic transformation. We find that in vitro transformation confers stem-cell properties to primary differentiated fibroblasts, including the ability to self-renew and to differentiate along multiple lineages. Tumours induced by transformed fibroblasts are hierarchically organized, and the cells that act as CSCs to initiate and maintain tumour growth are marked by the stage-specific embryonic antigen SSEA-1. Heterogeneous lineages of cancer cells in the bulk of the tumour arise through differentiation of SSEA-1+ fibroblasts, and differentiation is associated with loss of tumorigenic potential. These findings establish an experimental system to characterize cellular and molecular properties of human CSCs and demonstrate that somatic cells have the potential to de-differentiate and acquire properties of CSCs.

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Figure 1: Differentiation of in vitro-transformed fibroblasts.
Figure 2: The presence of the stage-specific embryonic antigen SSEA-1 in populations of differentiated cells correlates with acquisition of tumorigenicity on transformation.
Figure 3: SSEA-1 identifies a biologically distinct subpopulation of transformed fibroblasts.
Figure 4: SSEA-1+ fibroblasts are responsible for tumour initiation.
Figure 5: SSEA-1+ fibroblasts differentiate into non-fibroblastic cells during tumour growth.
Figure 6: Hierarchical organization of tumours induced byin vitro-transformed fibroblasts.
Figure 7: Self-renewal ability and evolution of SSEA-1+-transformed fibroblasts.
Figure 8: Model for reprogramming of somatic cells to CSCs.

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Acknowledgements

We thank J. Lee for instruction in mice injections, K. McKinnon (NCI CCR Vaccine Branch FACS Core Facility) for support with flow cytometry, P. Adams, R. A. Weinberg and L. Li for providing reagents and X. Wu for help with microarray analysis. This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), NCI, Center for Cancer Research.

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  1. National Cancer Institute, NIH, Bethesda, Maryland 20892, USA

    Paola Scaffidi & Tom Misteli

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  1. Paola Scaffidi
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P.S. conceived the study and carried out the experimental work. P.S. and T.M. designed the experiments and wrote the manuscript.

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Correspondence to Paola Scaffidi or Tom Misteli.

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Scaffidi, P., Misteli, T. In vitro generation of human cells with cancer stem cell properties. Nat Cell Biol 13, 1051–1061 (2011). https://doi.org/10.1038/ncb2308

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