Andalusian Stem Cell Bank, Centro de Investigación Biomédica, Consejería de Salud-Universidad de Granada, Granada, Spain.
Stem Cells. 2011 Feb;29(2):179-92. doi: 10.1002/stem.571.
Human sarcomas have been modeled in mice by expression of specific fusion genes in mesenchymal stem cells (MSCs). However, sarcoma models based on human MSCs are still missing. We attempted to develop a model of liposarcoma by expressing FUS (FUsed in Sarcoma; also termed TLS, Translocated in LipoSarcoma)-CHOP (C/EBP HOmologous Protein; also termed DDIT3, DNA Damage-Inducible Transcript 3), a hallmark mixoid liposarcoma-associated fusion oncogene, in wild-type and p53-deficient mouse and human adipose-derived mesenchymal stem/stromal cells (ASCs). FUS-CHOP induced liposarcoma-like tumors when expressed in p53(-/-) but not in wild-type (wt) mouse ASCs (mASCs). In the absence of FUS-CHOP, p53(-/-) mASCs forms leiomyosarcoma, indicating that the expression of FUS-CHOP redirects the tumor genesis/phenotype. FUS-CHOP expression in wt mASCs does not initiate sarcomagenesis, indicating that p53 deficiency is required to induce FUS-CHOP-mediated liposarcoma in fat-derived mASCs. In a human setting, p53-deficient human ASCs (hASCs) displayed a higher in vitro growth rate and a more extended lifespan than wt hASCs. However, FUS-CHOP expression did not induce further changes in culture homeostasis nor initiated liposarcoma in either wt or p53-depleted hASCs. These results indicate that FUS-CHOP expression in a p53-deficient background is sufficient to initiate liposarcoma in mouse but not in hASCs, suggesting the need of additional cooperating mutations in hASCs. A microarray gene expression profiling has shed light into the potential deregulated pathways in liposarcoma formation from p53-deficient mASCs expressing FUS-CHOP, which might also function as potential cooperating mutations in the transformation process from hASCs.
人类肉瘤已通过在间充质干细胞（MSCs）中表达特定融合基因在小鼠中建模。然而，基于人 MSC 的肉瘤模型仍然缺失。我们试图通过表达 FUS（肉瘤融合物；也称为 TLS，易位型脂肪肉瘤）-CHOP（C/EBP 同源物蛋白；也称为 DDIT3，DNA 损伤诱导的转录物 3），一种标志性的混合性脂肪肉瘤相关融合癌基因，在野生型和 p53 缺陷型小鼠和人脂肪来源的间充质干细胞/基质细胞（ASCs）中建立脂肪肉瘤模型。当在 p53（-/-）而非野生型（wt）小鼠 ASC 中表达时，FUS-CHOP 诱导脂肪肉瘤样肿瘤。在没有 FUS-CHOP 的情况下，p53（-/-）mASC 形成平滑肌肉瘤，表明 FUS-CHOP 的表达使肿瘤发生/表型发生重定向。FUS-CHOP 在 wt mASC 中的表达不会引发肉瘤发生，表明 p53 缺失是在脂肪源性 mASC 中诱导 FUS-CHOP 介导的脂肪肉瘤所必需的。在人类环境中，p53 缺陷型人 ASC（hASC）显示出比 wt hASC 更高的体外生长速度和更长的寿命。然而，FUS-CHOP 表达并未在 wt 或 p53 耗竭的 hASC 中进一步改变培养平衡，也未引发脂肪肉瘤。这些结果表明，在 p53 缺失背景下表达 FUS-CHOP 足以在小鼠中引发脂肪肉瘤，但在 hASC 中则不能，表明 hASC 中需要额外的协同突变。微阵列基因表达谱分析揭示了 FUS-CHOP 在表达 p53 缺陷型 mASC 中形成脂肪肉瘤的潜在失调途径，这些途径也可能在 hASC 转化过程中作为潜在的协同突变。
