β-catenin activation in a novel liver progenitor cell type is sufficient to cause hepatocellular carcinoma and hepatoblastoma.
β-catenin activation in a novel liver progenitor cell type is sufficient to cause hepatocellular carcinoma and hepatoblastoma.
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DOI：
10.1158/0008-5472.can-13-3275
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发表时间：
2014-08-15
期刊：
影响因子：
11.2
通讯作者：
Huff V
中科院分区：
文献类型：
--
作者：
Mokkapati S;Niopek K;Huang L;Cunniff KJ;Ruteshouser EC;deCaestecker M;Finegold MJ;Huff V
肝细胞癌在历史上被认为起源于肝细胞，但基因表达研究表明，它也可以起源于胎儿祖细胞或其成年祖细胞。在这里，我们报告了在小鼠中鉴定出一组独特的胎肝祖细胞，这些细胞可以作为肝细胞癌发展的起源细胞。在所使用的转基因模型中，小鼠携带Cited1-Creer™-GFP BAC转基因，其中他莫昔芬诱导的Cre(Creer™)和GFP由Cited1的一个190kb的5‘基因组区域控制，Cited1是CBP/p300的转录共激活蛋白。Wnt信号对调节前体/干细胞的自我更新至关重要，并与快速自我更新组织的癌症的病因有关，因此我们假设在Creer™-gfp+前体细胞中Wnt通路的激活将导致肝细胞癌。在小鼠模型的肝脏中，转基因表达细胞在E11.5时占肝细胞的4%，而其他标志物的表达是肝干细胞/祖细胞的特征，这些细胞产生成体肝细胞、胆管细胞和SOX9+导管周围细胞。到26周龄时，WNT途径激活的Cited1-Creer™-GFP；Ctnb1ex3(F1)小鼠中90%发展为肝癌，在某些情况下，肝母细胞瘤(HB)和肺转移。肝癌和HB在组织学上与人类相似，表现为Wnt、Ras/Raf/MAPK和PI3K/AKT/mTOR通路的激活，并表达相应的干/祖细胞标志。我们的结果表明，Wnt通路的激活足以使这些独特的肝祖细胞恶性转化，为某些人肝细胞癌的胎儿/成人祖细胞来源提供功能支持。我们相信，该模型可能为提高对肝细胞癌和乙肝的细胞病因学和生物学的了解以及开发针对这些疾病的改进的治疗方法提供一个有价值的新工具。
Hepatocellular carcinoma (HCC) was thought historically to arise from hepatocytes, but gene expression studies have suggested it can also arise from fetal progenitor cells or their adult progenitor progeny. Here we report the identification of a unique population of fetal liver progenitor cells in mice that can serve as a cell of origin in HCC development. In the transgenic model used, mice carry the Cited1-CreER™-GFP BAC transgene in which a tamoxifen-inducible Cre (CreER™) and GFP are controlled by a 190kb 5′ genomic region of Cited1, a transcriptional co-activator protein for CBP/p300. Wnt signaling is critical for regulating self-renewal of progenitor/stem cells and has been implicated in the etiology of cancers of rapidly self-renewing tissues, so we hypothesized that Wnt pathway activation in CreER™-GFP+ progenitors would result in HCC. In livers from the mouse model, transgene-expressing cells represented 4% of liver cells at E11.5 when other markers were expressed characteristic of the hepatic stem/progenitor cells that give rise to adult hepatocytes, cholangiocytes and SOX9+ periductal cells. By 26 weeks of age, >90% of Cited1-CreER™-GFP; Ctnnb1ex3(fl) mice with Wnt pathway activation developed HCC and, in some cases, hepatoblastomas (HB) and lung metastases. HCC and HB resembled their human counterparts histologically, showing activation of Wnt, Ras/Raf/MAPK and PI3K/AKT/mTOR pathways, and expressing relevant stem/progenitor cell markers. Our results show that Wnt pathway activation is sufficient for malignant transformation of these unique liver progenitor cells, offering functional support for a fetal/adult progenitor origin of some human HCC. We believe this model may offer a valuable new tool to improve understanding of the cellular etiology and biology of HCC and HB and the development of improved therapeutics for these diseases.