Sarcoma Derived from Cultured Mesenchymal Stem Cells

¹ Department of Pediatrics, Division of Hematology-Oncology, Blood and Marrow Transplant and Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota
² Laboratory of Experimental Hematology, Leiden University Medical Center, Leiden, the Netherlands
³ Graduate Program in Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School, Minneapolis, Minnesota
⁴ Department of Orthopedic Surgery, University of Minnesota Medical School, Minneapolis, Minnesota
⁵ Institute of Human Genetics, University of Minnesota Medical School, Minneapolis, Minnesota
⁶ Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
⁷ Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands
⁸ Institute of Human Genetics, University of Minnesota Medical School, Minneapolis, Minnesota; Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota
⁹ Departments of Pediatrics and Genetics, Stanford University School of Medicine, Stanford, California
¹⁰ Tulane School of Medicine, New Orleans, Louisiana

^* To whom correspondence should be addressed. E-mail: tolar003{at}umn.edu.

	Abstract

To study the biodistribution of Mesenchymal Stem Cells (MSCs), we labeled adult murine C57BL/6 MSCs with firefly luciferase and DsRed2 fluorescent protein using non-viral Sleeping Beauty transposons, and co-infused labeled MSCs with bone marrow into irradiated allogeneic recipients. Using in vivo whole body imaging, luciferase signals were shown to be increased between weeks 3 and 12. Unexpectedly, some mice with the highest luciferase signals died and all surviving mice developed foci of sarcoma in lungs. Two mice also developed sarcomas in their extremities. Common cytogenetic abnormalities were identified in tumor cells isolated from different animals. Original MSC cultures not labeled with transposons, as well as independently isolated cultured MSCs were found to be cytogenetically abnormal. Moreover, primary MSC's derived from the bone marrow of both BALB/c and C57BL/6 mice showed cytogenetic aberrations after several passages in vitro, showing that transformation was not a strain-specific nor rare event. Clonal evolution was observed in vivo suggesting that the critical transformation event(s) occurred before infusion. Mapping of the transposition insertion sites did not identify an obvious transposon related genetic abnormality and p53 was not overexpressed. Infusion of MSC-derived sarcoma cells resulted in malignant lesions in secondary recipients. This new sarcoma cell line, S1, is unique in having a cytogenetic profile similar to human sarcoma and contains bioluminescent and fluorescent genes making it useful for investigations of cellular biodistribution and tumor response to therapy in vivo. More importantly, our study indicates that sarcoma can evolve from MSC cultures.

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