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c-MYC overexpression with loss of Ink4a/Arf transforms bone marrow stromal cells into osteosarcoma accompanied by loss of adipogenesis

Oncogene volume 29, pages 5687–5699 (2010)Cite this article

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Abstract

The development of cancer is due to the growth and proliferation of transformed normal cells. Recent evidence suggests that the nature of oncogenic stress and the state of the cell of origin critically affect both tumorigenic activity and tumor histological type. However, this mechanistic relationship in mesenchymal tumors is currently largely unexplored. To clarify these issues, we established a mouse osteosarcoma (OS) model through overexpression of c-MYC in bone marrow stromal cells (BMSCs) derived from Ink4a/Arf (−/−) mice. Single-cell cloning revealed that c-MYC-expressing BMSCs are composed of two distinctly different clones: highly tumorigenic cells, similar to bipotent-committed osteochondral progenitor cells, and low-tumorigenic tripotent cells, similar to mesenchymal stem cells (MSCs). It is noteworthy that both bipotent and tripotent cells were capable of generating histologically similar, lethal OS, suggesting that both committed progenitor cells and MSCs can become OS cells of origin. Shifting mesenchymal differentiation by depleting PPARγ in tripotent MSC-like cells and overexpressing PPARγ in bipotent cells affected cell proliferation and tumorigenic activity. Our findings indicate that differentiation potential has a key role in OS tumorigenic activity, and that the suppression of adipogenic ability is a critical factor for the development of OS.

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Acknowledgements

We are grateful to I Ishimatsu and N Suzuki for technical assistance. We thank K Arai for secretarial assistance. This work was partly supported by grants from the Ministry of Education, Science, Sports, and Culture of Japan (TS and HS) and a grant from the National Institute of Biomedical Innovation, Japan (HS).

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Authors and Affiliations

  1. Division of Gene Regulation, Institute for Advanced Medical Research, Keio University, Tokyo, Japan

    T Shimizu, T Ishikawa, E Sugihara, S Kuninaka & H Saya

  2. CREST, Japan Science and Technology Agency, Tokyo, Japan

    T Shimizu, E Sugihara & H Saya

  3. Kasai R&D Center, Daiichi Sankyo Co Ltd, Tokyo, Japan

    T Ishikawa

  4. Department of Orthopedic Surgery, Keio University, Tokyo, Japan

    T Miyamoto, H Morioka, R Nakayama, E Kobayashi & Y Toyama

  5. Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama, Japan

    T Miyamoto

  6. Department of Physiology, Keio University, Tokyo, Japan

    Y Mabuchi & Y Matsuzaki

  7. Center for Genomic Medicine, RIKEN, Yokohama, Japan

    T Tsunoda & F Miya

  8. Orthopedics Division, National Cancer Center Hospital, Tokyo, Japan

    A Kawai

  9. Cancer Transcriptome Project, National Cancer Center Research Institute, Tokyo, Japan

    H Ichikawa

  10. Department of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan

    T Hasegawa

  11. Division of Hematopoiesis, Center for AIDS Research, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

    S Okada

  12. Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

    T Ito

  13. Department of Internal Medicine, Keio University, Tokyo, Japan

    Y Ikeda

  14. Department of Cell Differentiation, The Sakaguchi Laboratory, Keio University, Tokyo, Japan

    T Suda

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Correspondence to H Saya.

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Shimizu, T., Ishikawa, T., Sugihara, E. et al. c-MYC overexpression with loss of Ink4a/Arf transforms bone marrow stromal cells into osteosarcoma accompanied by loss of adipogenesis. Oncogene 29, 5687–5699 (2010). https://doi.org/10.1038/onc.2010.312

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