Transformation of human mesenchymal stem cells in radiation carcinogenesis: long-term effect of ionizing radiation

摘要

Increasing evidence on cancer stem cells suggest that stem cells are susceptive to carcinogenesis andconsequently can be the origin of many cancers. We have recently established a telomerase-transducedhuman mesenchymal stem cell line and subsequently irradiated this in order to achieve malignanttransformation. In the present study, we analyzed the long-term effect of ionizing radiation on these cellsand investigate whether radiation can trigger tumor development. The cells were irradiated with a low(2.5 Gy) and a high (15 Gy) dose of γ-rays and followed for up to 6 months after radiation. A subclone ofthe cells irradiated with 2.5 Gy of γ-rays formed tumors after implantation to severe combinedimmunodefi ciency mice. During the process of transformation, the cells showed accelerated telomereshortening, increased levels of anaphase bridges and a shift from balanced to unbalanced translocations.The tumor suppressor genes p53 and p21CIP1 functioned normally throughout the study. Our observationsindicate that radiation destabilized the telomeres and that the presence of uncapped telomeres initiatedfusion-break-fusion cycles, resulting in increased chromosomal instability and tumor formation. Thus,bone marrow-derived human mesenchymal stem cells are capable of exhibiting a malignant phenotype.