TY - JOUR
T1 - C-MYC overexpression with loss of Ink4a/Arf transforms bone marrow stromal cells into osteosarcoma accompanied by loss of adipogenesis
AU - Shimizu, T.
AU - Ishikawa, T.
AU - Sugihara, E.
AU - Kuninaka, S.
AU - Miyamoto, T.
AU - Mabuchi, Y.
AU - Matsuzaki, Y.
AU - Tsunoda, T.
AU - Miya, F.
AU - Morioka, H.
AU - Nakayama, R.
AU - Kobayashi, E.
AU - Toyama, Y.
AU - Kawai, A.
AU - Ichikawa, H.
AU - Hasegawa, T.
AU - Okada, S.
AU - Ito, T.
AU - Ikeda, Y.
AU - Suda, T.
AU - Saya, H.
N1 - Funding Information:
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).
PY - 2010/10/21
Y1 - 2010/10/21
N2 - 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.
AB - 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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U2 - 10.1038/onc.2010.312
DO - 10.1038/onc.2010.312
M3 - Article
C2 - 20676132
AN - SCOPUS:77958493016
VL - 29
SP - 5687
EP - 5699
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 42
ER -