PDF(Pubmed)
Abstract：
Desmoplastic Small Round Cell Tumor (DSRCT) is a rare and aggressive pediatric cancer driven by the EWSR1-WT1 fusion oncogene. Combinations of chemotherapy, radiation and surgery are not curative, and the 5-years survival rate is less than 25%. One potential explanation for refractoriness is the existence of a cancer stem cell (CSC) subpopulation able escape current treatment modalities. However, no study to-date has examined the role of CSCs in DSRCT or established in vitro culture conditions to model this subpopulation. In this study, we investigated the role of stemness markers in DSRCT survival and metastasis, finding that elevated levels of SOX2 and NANOG are associated with worse survival in sarcoma patients and are elevated in metastatic DSRCT tumors. We further develop the first in vitro DSRCT CSC model which forms tumorspheres, expresses increased levels of stemness markers (SOX2, NANOG, KLF4, and OCT4), and resists doxorubicin chemotherapy treatment. This model is an important addition to the DSRCT tool kit and will enable investigation of this critical DSRCT subpopulation. Despite lower sensitivity to chemotherapy, the DSRCT CSC model remained sensitive to knockdown of the EWSR1-WT1 fusion protein, suggesting that future therapies directed against this oncogenic driver have the potential to treat both DSRCT bulk tumor and CSCs.
摘要：
促纤维增生性小圆细胞肿瘤（DSRCT）是由EWSR1-WT1融合癌基因驱动的一种罕见且侵袭性的儿科癌症。联合化疗，辐射和手术都不能治愈，5年生存率低于25%。难治性的一种潜在解释是存在能够逃避当前治疗方式的癌症干细胞（CSC）亚群。然而,迄今为止,还没有一项研究对CSC在DSRCT中的作用进行研究,也没有建立体外培养条件对该亚群进行建模.在这项研究中,我们研究了干性标志物在DSRCT生存和转移中的作用，发现SOX2和NANOG水平升高与肉瘤患者的生存率较差相关，而在转移性DSRCT肿瘤中，SOX2和NANOG水平升高。我们进一步开发了第一个形成肿瘤球的体外DSRCTCSC模型，表达水平增加的干性标记(SOX2，NANOG，KLF4和OCT4），并抵抗阿霉素化疗治疗。该模型是DSRCT工具包的重要补充，将能够对这一关键DSRCT亚群进行调查。尽管对化疗的敏感性较低，DSRCTCSC模型仍然对EWSR1-WT1融合蛋白的敲低敏感，这表明，针对这种致癌驱动因素的未来疗法有可能治疗DSRCT大块肿瘤和CSC。
