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Human osteosarcoma CD49fCD133+ cells: impaired in osteogenic fate while gain of tumorigenicity

Abstract

The biological relationships among self-renewal, tumorigenicity and lineage differentiation of human osteosarcoma-initiating cells (OSIC) remain elusive, making it difficult to identify and distinguish OSIC from osteosarcoma-forming cells (OSFC) for developing OSIC-targeted therapies. Using a new inverse-lineage tracking strategy coupled with serial human-to-mouse xenotransplantation, we identified a subpopulation of osteosarcoma cells with OSIC-like properties and sought to distinguish them from their progeny, OSFC. We found that serial transplantation of cells from different osteosarcoma cell lines and primary osteosarcoma tissues progressively increased the CD49f+ subpopulation composing the bulk of the osteosarcoma mass. These CD49f+ cells displayed characteristics of OSFC: limited in vivo tumorigenicity, weak lineage differentiation, more differentiated osteogenic feature and greater chemo-sensitivity. By contrast, their parental CD49fCD133+ cells had an inhibited osteogenic fate, together with OSIC-like properties of self-renewal, strong tumorigenicity and differentiation to CD49f+ progeny. Hence, the CD49fCD133+ phenotype appears to identify OSIC-like cells that possess strong tumorigenicity correlated with an impaired osteogenic fate and the ability to initiate tumor growth through the generation of CD49f+ progeny. These findings advance our understanding of OSIC-like properties and, for the first time, provide a much-needed distinction between OSIC and OSFC in this cancer.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (R01 CA120512 and ARRA-R01CA120512 to LW).

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Correspondence to L Wu.

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Ying, M., Liu, G., Shimada, H. et al. Human osteosarcoma CD49fCD133+ cells: impaired in osteogenic fate while gain of tumorigenicity. Oncogene 32, 4252–4263 (2013). https://doi.org/10.1038/onc.2012.438

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