2009 Fiscal Year Final Research Report
Establishment and analysis of mouse tumor models from multipotent bone marrow stromal cells overexpressing c-MYC
| Project/Area Number |
20790310
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Experimental pathology
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| Research Institution | Keio University |
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Principal Investigator |
SHIMIZU Takatsune Keio University, 医学部, 助教 (40407101)
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| Project Period (FY) |
2008 – 2009
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| Keywords | 腫瘍 |
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| Research Abstract |
By overexpressing c-MYC in mouse bone marrow stromal cells (BMSCs) derived from Ink4a/Arf (-/-) mice, we generated mouse osteosarcoma in vitro. To clarify the cells of origin of OS, we performed single cell cloning. According to differentiation potentials, those c-MYC expressing BMSCs were composed of two distinctly-different clones: bipotent (osteogenic and chondrogenic) cells designated AX cells and tripotent (adipogenic, osteogenic, and chondrogenic) cells termed AO cells. AX cells were derived form osteo-chondro-committed progenitor cells, while AO cells were originated from MSCs. Bipotent AX cells were highly tumorigenic and possessed high propensity for distant metastasis that mimics human disease. In addition, they showed both terminal differentiation and self-renewal capacity in vivo, which are properties ascribed to cancer stem cell. Notably, tripotent AO cells also developed lethal OS in syngeneic mice more slowly and less frequently than AX cells. Moreover, during OS development tripotent AO cells lost their adipogenic potential and transformed into AX-like cells in vivo. Thus, the loss of adipogenic potential was suggested to be an essential event for OS development. The PPARγ knockdown afforded tripotent AO cells the advantage to OS formation in both differentiation and proliferation. In contrast, overexpression of PPARγ in bipotent AX cells attenuated their tumorigenic activities. Therefore, our findings indicated that differentiation potentials played key roles on the tumor initiating activity and lineage commitment to osteocyte might be a critical factor for the OS development.
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