Accumulated chromosomal instability in murine bone marrow mesenchymal stem cells leads to malignant transformation

Masako Miura, Yasuo Miura, Hesed M. Padilla-Nash, Alfredo A. Molinolo, Baojin Fu, Vyomesh Patel, Byoung Moo Seo, Wataru Sonoyama, Jenny J. Zheng, Carl C. Baker, Wanjun Chen, Thomas Ried, Songtao Shi

Research output: Contribution to journalArticlepeer-review

458 Citations (Scopus)

Abstract

Despite recent emerging evidence suggesting that cancer stem cells subsist in a variety of tumors, it is not yet fully elucidated whether postnatal stem cells are directly involved in tumorigenesis. We used murine bone marrow-derived mesenchymal stem cells (BMMSCs) as a model to test a hypothesis that tumorigenesis may originate from spontaneous mutation of stem cells. In this study, we demonstrated that murine BMMSCs, after numerous passages, obtained unlimited population doublings and proceeded to a malignant transformation state, resulting in fibrosarcoma formation in vivo. Transformed BMMSCs colonized to multiple organs when delivered systemically through the tail vein. Fibrosarcoma cells formed by transformed BMMSCs contained cancer progenitors, which were capable of generating colony clusters in vitro and fibrosarcoma in vivo by the second administration. The mechanism by which BMMSCs transformed to malignant cells was associated with accumulated chromosomal abnormalities, gradual elevation in telomerase activity, and increased c-myc expression. Moreover, BMMSCs and their transformed counterpart, fibrosarcoma-forming cells, demonstrated different sensitivity to anti-cancer drugs. BMMSCs/fibrosarcoma transformation system may provide an ideal system to elucidate the mechanism of how stem cells become cancer cells and to screen anti-sarcoma drugs.

Original languageEnglish
Pages (from-to)1095-1103
Number of pages9
JournalStem Cells
Volume24
Issue number4
DOIs
Publication statusPublished - 04-2006

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

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