Genetically transforming human mesenchymal stem cells to sarcomas: Changes in cellular phenotype and multilineage differentiation potential

BACKGROUND: The cell of origin of sarcoma is still unclear. High-grade osteosarcomas frequently demonstrate the potential for multipotent differentiation and, along with several other lines of evidence, suggest that human mesenchymal stem cells (hMSC) might be the cell of origin. METHODS: The hMSCs were transformed with retrovirus containing human telomerase reverse transcriptase (hTERT), simian virus 40 large t antigen (SV40 TAg), and lentivirus containing oncogenic H-Ras serially. The changes of cellular phenotypes and multilineage differentiation capacity were observed and compared with the standard osteosarcoma cell lines. RESULTS: Two distinct genotypic and phenotypic sarcoma cell lines resulted from the same genetic events. The gene expression profiles became more complicated and the karyotype became more chaotic during hMSCs' tumorigenesis. The motility of transformed hMSC was promoted. hMSC and its derivatives could be induced to osteogenic, adipogenic, and chondrogenic differentiation except that MSCTSR4 lost osteogenic differentiation capacity. CONCLUSIONS: Multilineage differentiation potential was retained during tumorigenesis of hMSCs and distinct sarcoma cell lines could arise with the same genetic events, providing good models in better understanding the concept of hMSC and in further investigation of the relationship of hMSCs and osteosarcomas.