CD24+ Liver Tumor-Initiating Cells Drive Self-Renewal and Tumor Initiation through STAT3-Mediated NANOG Regulation
CD24+ Liver Tumor-Initiating Cells Drive Self-Renewal and Tumor Initiation through STAT3-Mediated NANOG Regulation
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DOI：
10.1016/j.stem.2011.06.005
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发表时间：
2011-07-08
期刊：
影响因子：
23.9
通讯作者：
Irene Oi Lin Ng
中科院分区：
文献类型：
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作者：
Lee, Terence Kin Wah;Castilho, Antonia;Irene Oi Lin Ng
肿瘤起始细胞（T-IC）是化疗耐药肿瘤细胞的亚群，已显示其在化疗后引起肿瘤复发。因此，识别T-IC及其相关通路是开发新治疗模式的优先事项。我们在免疫功能低下的小鼠中建立了耐药肝细胞癌（HCC）异种移植瘤，其中富集的T-IC群体能够引发肿瘤并自我更新。利用该模型，我们发现与顺铂治疗后的大部分肿瘤相比，在残留的化疗耐药肿瘤中CD 24上调。CD 24（+）HCC细胞被发现对于肿瘤的维持、自我更新、分化和转移至关重要，并显著影响患者的临床结果。利用基于慢病毒的敲低方法，发现CD 24是通过STAT 3介导的NANOG调节驱动T-IC发生的功能性肝脏T-IC标志物。我们的研究结果指出，肝脏T-IC中的CD 24级联可能为HCC患者提供有吸引力的治疗靶点。
Tumor-initiating cells (T-ICs) are a subpopulation of chemoresistant tumor cells that have been shown to cause tumor recurrence upon chemotherapy. Identification of T-ICs and their related pathways are therefore priorities for the development of new therapeutic paradigms. We established chemoresistant hepatocellular carcinoma (HCC) xenograft tumors in immunocompromised mice in which an enriched T-IC population was capable of tumor initiation and self-renewal. With this model, we found CD24 to be upregulated in residual chemoresistant tumors when compared with bulk tumor upon cisplatin treatment. CD24(+) HCC cells were found to be critical for the maintenance, self-renewal, differentiation, and metastasis of tumors and to significantly impact patients' clinical outcome. With a lentiviral-based knockdown approach, CD24 was found to be a functional liver T-IC marker that drives T-IC genesis through STAT3-mediated NANOG regulation. Our findings point to a CD24 cascade in liver T-ICs that may provide an attractive therapeutic target for HCC patients.