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

T. Shimizu, T. Ishikawa, E. Sugihara, S. Kuninaka, T. Miyamoto, Y. Mabuchi, Y. Matsuzaki, T. Tsunoda, F. Miya, H. Morioka, R. Nakayama, E. Kobayashi, Y. Toyama, A. Kawai, H. Ichikawa, T. Hasegawa, S. Okada, T. Ito, Y. Ikeda, T. SudaH. Saya

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)5687-5699
Number of pages13
JournalOncogene
Volume29
Issue number42
DOIs
StatePublished - Oct 21 2010

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Adipogenesis
Osteosarcoma
Mesenchymal Stromal Cells
Peroxisome Proliferator-Activated Receptors
Stem Cells
Neoplasms
Organism Cloning
Clone Cells
Cell Proliferation

Keywords

  • PPARγ
  • animal model
  • differentiation
  • osteosarcoma

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

C-MYC overexpression with loss of Ink4a/Arf transforms bone marrow stromal cells into osteosarcoma accompanied by loss of adipogenesis. / Shimizu, T.; Ishikawa, T.; Sugihara, E.; Kuninaka, S.; Miyamoto, T.; Mabuchi, Y.; Matsuzaki, Y.; Tsunoda, T.; Miya, F.; Morioka, H.; Nakayama, R.; Kobayashi, E.; Toyama, Y.; Kawai, A.; Ichikawa, H.; Hasegawa, T.; Okada, S.; Ito, T.; Ikeda, Y.; Suda, T.; Saya, H.

In: Oncogene, Vol. 29, No. 42, 21.10.2010, p. 5687-5699.

Research output: Contribution to journalArticle

Shimizu, T, Ishikawa, T, Sugihara, E, Kuninaka, S, Miyamoto, T, Mabuchi, Y, Matsuzaki, Y, Tsunoda, T, Miya, F, Morioka, H, Nakayama, R, Kobayashi, E, Toyama, Y, Kawai, A, Ichikawa, H, Hasegawa, T, Okada, S, Ito, T, Ikeda, Y, Suda, T & Saya, H 2010, 'C-MYC overexpression with loss of Ink4a/Arf transforms bone marrow stromal cells into osteosarcoma accompanied by loss of adipogenesis', Oncogene, vol. 29, no. 42, pp. 5687-5699. https://doi.org/10.1038/onc.2010.312
Shimizu, T. ; Ishikawa, T. ; Sugihara, E. ; Kuninaka, S. ; Miyamoto, T. ; Mabuchi, Y. ; Matsuzaki, Y. ; Tsunoda, T. ; Miya, F. ; Morioka, H. ; Nakayama, R. ; Kobayashi, E. ; Toyama, Y. ; Kawai, A. ; Ichikawa, H. ; Hasegawa, T. ; Okada, S. ; Ito, T. ; Ikeda, Y. ; Suda, T. ; Saya, H. / C-MYC overexpression with loss of Ink4a/Arf transforms bone marrow stromal cells into osteosarcoma accompanied by loss of adipogenesis. In: Oncogene. 2010 ; Vol. 29, No. 42. pp. 5687-5699.
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AU - Kuninaka, S.

AU - Miyamoto, T.

AU - Mabuchi, Y.

AU - Matsuzaki, Y.

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AU - Miya, F.

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AU - Kawai, A.

AU - Ichikawa, H.

AU - Hasegawa, T.

AU - Okada, S.

AU - Ito, T.

AU - Ikeda, Y.

AU - Suda, T.

AU - Saya, H.

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