Multistep carcinogenesis of perihilar cholangiocarcinoma arising in the intrahepatic large bile ducts
Multistep carcinogenesis of perihilar cholangiocarcinoma arising in the intrahepatic large bile ducts
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DOI：
10.4254/wjh.v1.i1.35
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发表时间：
2009-10-31
影响因子：
2.4
通讯作者：
Harada, Kenichi
中科院分区：
文献类型：
--
作者：
Nakanuma, Yasuni;Sasaki, Motoko;Harada, Kenichi
扁平型“胆管上皮内瘤变(BLIN)”和乳头型“胆管内乳头状瘤(IPN-B)”被认为是侵袭性肝门部肝内胆管癌(ICC)的先兆。提出了三条致癌途径：胆林向管状腺癌发展，IPN-B向管状腺癌或胶质癌发展。粘蛋白核心蛋白2-/细胞角蛋白20-(MUC2-/CK20-)可导致MUC1表达，而IPN-B可导致管状腺癌或MUC1阴性的胶体癌。在BLIN和IPNB系列中，p21、P53和细胞周期蛋白D1的表达随着组织学进展而上调。有趣的是，P53在BLIN侵袭期表达上调，而在非侵袭性BLIN中低表达，而P53在IPN-B1中表达上调，在IPN-B2和侵袭性ICC中达到平台期。P16(INK4a)在BLIN-2/3和浸润性癌中的表达明显降低，p16(INK4a)在BI-LIN1中的表达减少。EZH2的表达从胆林癌到浸润性癌呈递增趋势。胆林组ICC中β-连环蛋白和E-钙粘附素的膜表达较IPNB组明显减少。有趣的是，β-连环素和E-钙粘附素膜分布的破坏似乎导致了表达MMP7和MT1-MMP2的BLIN和IPN-B癌细胞的侵袭和转移。细胞周期蛋白D1和c-myc的表达增加在IPNB谱系中比在Blin谱系中更常见，可能与Wnt信号通路有关，与β-catenin的核积累有关。总之，BLIN和IPN-B通过特有的多步骤过程进展为侵袭性ICC。(C)2009年白石登。版权所有。
Flat-type "biliary intraepithelial neoplasia (BilIN)" and papillary-type " intraductal papillary neoplasm of the bile duct (IPN-B)" are proposed as precursors of invasive, perihilar intrahepatic cholangiocarcinoma (ICC). Three carcinogenetic pathways are proposed: BilIN progressing to tubular adenocarcinoma, and IPN-B progressing to tubular adenocarcinoma or to colloid carcinoma. Carcinogenesis via BilIN was characterized by mucin core protein 2-/cytokeratin 20-(MUC2-/CK20-) with MUC1 expression, while carcinogenesis via IPN-B leading to tubular adenocarcinoma was associated with MUC1 expression or that to colloid carcinoma with MUC1-negativity. In both the BilIN and IPNB series, the expression of p21, p53, and cyclin D1 was upregulated with histological progression. Interestingly, p53 expression was upregulated at the invasive stage of BilIN, but was low in noninvasive BilIN, while p53 expression was upregulated in IPN-B1 and reached a plateau in IPN-B2 and invasive ICC. Expression of p16(INK4a), which was frequent in Bi-lIN1, was decreased in BilIN-2/3 and invasive carcinoma. EZH2 expression showed a stepwise increase from BilIN to invasive carcinoma. Membranous expression of beta-catenin and E-cadherin was more markedly decreased in ICC with BilIN than in ICC with IPNB. Interestingly, disruption of the membranous distribution of beta-catenin and E-cadherin seems to result in the invasion and metastasis of carcinoma cells of BilIN and IPN-B expressing MMP-7 and MT1-MMP. Increased expression of cyclin D1 and c-myc was more frequent in the IPNB lineage than BilIN lineage, possibly related to the Wnt signaling pathway associated with the nuclear accumulation of beta-catenin. In conclusion, BilIN and IPN-B progress to invasive ICC through characteristic multistep processes. (C) 2009 Baishideng. All rights reserved.