Sarcoma Derived from Cultured Mesenchymal Stem Cells

Abstract

To study the biodistribution of MSCs, we labeled adult murine C57BL/6 MSCs with firefly luciferase and DsRed2 fluorescent protein using nonviral Sleeping Beauty transposons and coinfused 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 their 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 MSCs 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 transposonrelated 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. STEM CELLS 2007;25:371-379

Stromal cells–are they really useful for GVHD?

“…104 Patients treated with stromal cells need to be followed closely for the possible risk of tumor formation. 25,26,[105][106][107][108] When taking all clinical observations into consideration, we still believe that stromal cell therapy can be useful for GVHD, particularly in children. However, this treatment needs to be optimized, combining it with the right immunosuppressive therapies.…”

Modeling sarcomagenesis using multipotent mesenchymal stem cells

“…Upon inoculation into immunodeficient mice, spontaneously transformed mMSCs promote the formation of sarcomas resembling the histopathological properties of fibrosarcoma [15,16] and osteosarcoma [17,18]. In these reports, the transformation of mMSCs was associated with the accumulation of chromosome instability [16][17][18][19], p53 mutations [15] or loss of CDKN2A/p16 [17], highlighting the importance of a tight cell cycle control in MSC homeostasis.…”

“…Mouse MSCs Mouse MSCs (mMSCs) are especially predisposed to acquiring transformation events after long-term in vitro culture favoring clonal selection of transformed cells [15][16][17][18][19] (Table 1). Upon inoculation into immunodeficient mice, spontaneously transformed mMSCs promote the formation of sarcomas resembling the histopathological properties of fibrosarcoma [15,16] and osteosarcoma [17,18].…”

Osteosarcoma

“…(17) A separate line of evidence comes from the observation that serially passaged murine mesenchymal stem cells will undergo rare spontaneous transformation resulting in an osteosarcoma-like tumor, suggesting that these cells are the cell of origin. (18,19) With the existing available data, it is not possible to define whether osteosarcoma derives from mesenchymal stem cells or a more differentiated progenitor. The rarity of osteosarcoma may be related to a small pool of cells being capable of producing the cancer.…”