Spontaneous expression of embryonic factors and p53 point mutations in aged mesenchymal stem cells: A model of age-related tumorigenesis in mice
Spontaneous expression of embryonic factors and p53 point mutations in aged mesenchymal stem cells: A model of age-related tumorigenesis in mice
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DOI：
10.1158/0008-5472.can-07-2665
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发表时间：
2007-11-15
期刊：
影响因子：
11.2
通讯作者：
Houghton, JeanMarie
中科院分区：
文献类型：
--
作者：
Li, Hanchen;Fan, Xueli;Houghton, JeanMarie
衰老是癌症最常见的风险因素。外周和骨髓来源的干细胞是长寿的，并且是癌症起始细胞的候选细胞。重复的复制可能需要积累必要的基因突变。基于间充质干细胞（MSC）转化频率高于其他细胞类型的事实，以及老年C57 BL/6小鼠中的肿瘤通常是纤维肉瘤，我们使用基因标记的骨髓（BM）移植模型来显示老年小鼠发生MSC衍生的纤维肉瘤。我们进一步表明，随着年龄的增长，MSC在培养中自发转化，当置于我们的小鼠模型中时，重现了老年小鼠自然发生的纤维肉瘤，其基因表达变化和p53突变与体内模型相似。自发转化的MSC直接贡献于肿瘤、肿瘤脉管系统和肿瘤脂肪组织，募集额外的宿主BM衍生细胞（BMDC）到该区域，并与宿主BMDC融合。未融合的转化MSC充当癌症干细胞，并且能够在连续小鼠中形成肿瘤，而融合恢复非恶性表型。这些数据表明，间充质干细胞可能在年龄相关性肿瘤中发挥关键作用，与宿主细胞融合可恢复非恶性表型，从而提供调节肿瘤细胞活性的机制。
Aging is the single most common risk factor for cancer. Peripheral and marrow-derived stem cells are long lived and are candidate cells for the cancer-initiating cell. Repeated rounds of replication are likely required for accumulation of the necessary genetic mutations. Based on the facts that mesenchymal stem cells (MSC) transform with higher frequency than other cell types, and tumors in aged C57BL/6 mice are frequently fibrosarcomas, we used a genetically tagged bone marrow (BM) transplant model to show that aged mice develop MSC-derived fibrosarcomas. We further show that, with aging, MSCs spontaneously transform in culture and, when placed into our mouse model, recapitulated the naturally occurring fibrosarcomas of the aged mice with gene expression changes and p53 mutation similar to the in vivo model. Spontaneously transformed MSCs contribute directly to the tumor, tumor vasculature, and tumor adipose tissue, recruit additional host BM-derived cells (BMDC) to the area, and fuse with the host BMDC. Unfused transformed MSCs act as the cancer stem cell and are able to form tumors in successive mice, whereas fusion restores a nonmalignant phenotype. These data suggest that MSCs may play a key role in age-related tumors, and fusion with host cells restores a nonmalignant phenotype, thereby providing a mechanism for regulating tumor cell activity.