Model of fibrolamellar hepatocellular carcinomas reveals striking enrichment in cancer stem cells.
Model of fibrolamellar hepatocellular carcinomas reveals striking enrichment in cancer stem cells.
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DOI：
10.1038/ncomms9070
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发表时间：
2015-10-06
影响因子：
16.6
通讯作者：
Reid LM
中科院分区：
文献类型：
--
作者：
Oikawa T;Wauthier E;Dinh TA;Selitsky SR;Reyna-Neyra A;Carpino G;Levine R;Cardinale V;Klimstra D;Gaudio E;Alvaro D;Carrasco N;Sethupathy P;Reid LM
人类纤维板层状肝细胞癌(HFL-HCCs)是一种越来越多发生在儿童到年轻人的癌症，其病因学目前还知之甚少。我们提出了一种可移植的肿瘤系，维持在免疫低下的小鼠身上，并通过多种方法验证它是真正的HFL-HC模型。RNA-seq分析证实存在HFL-HCC肿瘤特有的融合转录本(DNAJB1-PRKACA)。有限稀释肿瘤致瘤性分析、球体形成和流式细胞术表明，HFL-HCC肿瘤细胞系高度富含癌症干细胞。在HFL-HCC模型上的免疫组织化学，以及对27个原发HFL-HCC肿瘤的平行研究，为内皮干细胞特征的表达提供了强有力的证据。对肿瘤系和多个正常肝脏谱系阶段的转录分析显示，HFL-HC的基因特征与胆汁树干细胞非常相似--胆树干细胞是新发现的肝脏和胰腺的前体细胞。这一模型为研究HFL-HC的发病机制和潜在的治疗方法提供了前所未有的机会。由于没有可用的细胞系，研究人纤维板层状肝细胞癌(HFL-HCCs)的病因学已被证明是有问题的。在这里，Oikawa等人。建立HFL-HC模型，作为免疫受损小鼠体内维持的可移植肿瘤系，证明其含有丰富的肿瘤干细胞。
The aetiology of human fibrolamellar hepatocellular carcinomas (hFL-HCCs), cancers occurring increasingly in children to young adults, is poorly understood. We present a transplantable tumour line, maintained in immune-compromised mice, and validate it as a bona fide model of hFL-HCCs by multiple methods. RNA-seq analysis confirms the presence of a fusion transcript (DNAJB1-PRKACA) characteristic of hFL-HCC tumours. The hFL-HCC tumour line is highly enriched for cancer stem cells as indicated by limited dilution tumourigenicity assays, spheroid formation and flow cytometry. Immunohistochemistry on the hFL-HCC model, with parallel studies on 27 primary hFL-HCC tumours, provides robust evidence for expression of endodermal stem cell traits. Transcriptomic analyses of the tumour line and of multiple, normal hepatic lineage stages reveal a gene signature for hFL-HCCs closely resembling that of biliary tree stem cells—newly discovered precursors for liver and pancreas. This model offers unprecedented opportunities to investigate mechanisms underlying hFL-HCCs pathogenesis and potential therapies. With no cell lines available, investigating the aetiology of human fibrolamellar hepatocellular carcinomas (hFL-HCCs) has proved problematic. Here, Oikawa et al. establish a model of hFL-HCCs as a transplantable tumour line maintained in immune-compromised mice, which proves rich in cancer stem cells.