Proliferating EpCAM-Positive Ductal Cells in the Inflamed Liver Give Rise to Hepatocellular Carcinoma
Proliferating EpCAM-Positive Ductal Cells in the Inflamed Liver Give Rise to Hepatocellular Carcinoma
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DOI：
10.1158/0008-5472.can-17-1800
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发表时间：
2017-11-15
期刊：
影响因子：
11.2
通讯作者：
Marusawa, Hiroyuki
中科院分区：
文献类型：
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作者：
Matsumoto, Tomonori;Takai, Atsushi;Marusawa, Hiroyuki
肝细胞癌（HCC）起源于慢性炎症肝脏中具有遗传改变的再生肝细胞。胆管细胞和肝细胞在肝脏再生中增殖，来源于胆管的增殖性胆管细胞（PDC）一直被认为是假定的肝干/祖细胞和HCC的候选细胞起源。然而，与越来越多的证据表明HCC起源于肝细胞相比，PDC作为肿瘤起源细胞的潜力仍然存在争议。在这里，我们证明表达既定表面和癌症干细胞标记EpCAM的PDCs在发炎的肝脏中引起HCC。在新开发的EpcamCreERT2小鼠中特异性标记表达epcam的PDCs，并在化学诱导的肝损伤模型中进行追踪。利用条件转基因小鼠，通过激活诱导胞苷脱氨酶的诱变活性诱导epcam阳性细胞的遗传改变逐步积累。谱系示踪实验显示，在化学损伤的肝脏中，标记的PDC分化为胆管细胞，而不分化为肝细胞。然而，epcam阳性的PDC基因改变在给药8个月后引起HCC。pdc来源的HCC表现出与人胆管细胞癌（CLC）相似的伴发小管样结构的组织学特征，并表现出从pdc样CLC细胞向肝细胞样HCC细胞的一系列转变。Wnt信号通路在pdc源性HCC的CLC组分中特异性上调。我们的研究结果提供了直接的实验证据，表明表达epcam的PDC可能是HCC的细胞起源，表明存在干细胞/祖源性肝癌发生。(c) 2017 aacr。
Hepatocellular carcinoma (HCC) originates from regenerating liver cells with genetic alterations in chronically inflamed liver. Ductal cells and hepatocytes proliferate for liver regeneration, and proliferating ductal cells (PDC) derived from bile ductules have long been considered putative liver stem/progenitor cells and candidate cellular origins of HCC. The potential of PDC as tumororiginating cells, however, remains controversial in contrast to accumulating evidence that HCC originates from hepatocytes. Here, we demonstrate that PDCs expressing the established surface and cancer stem cell marker EpCAM give rise to HCC in inflamed liver. EpCAM-expressing PDCs were specifically labeled in newly developed EpcamCreERT2 mice and traced in a chemically induced liver injury model. Stepwise accumulation of genetic alterations in EpCAM-positive cells was induced by the mutagenesis activity of activation-induced cytidine deaminase using conditional transgenic mice. Lineage-tracing experiments revealed that labeled PDC differentiated into cholangiocytes, but not into hepatocytes, in the chemically damaged liver. Nevertheless, EpCAM-positive PDC with genetic alterations gave rise to HCC after 8 months of chemical administration. PDC-derived HCC showed histologic characteristics of concomitant ductule-like structures resembling human cholangiolocellular carcinoma (CLC) and exhibited serial transitions from PDC-like CLC cells to hepatocyte-like HCC cells. The Wnt signaling pathway was specifically upregulated in the CLC components of PDC-derived HCC. Our findings provide direct experimental evidence that EpCAM-expressing PDC could be a cellular origin of HCC, suggesting the existence of stem/ progenitor-derived hepatocarcinogenesis. (C) 2017 AACR.