Chronic bile duct injury associated with fibrotic matrix microenvironment provokes cholangiocarcinoma in p53-deficient mice
Chronic bile duct injury associated with fibrotic matrix microenvironment provokes cholangiocarcinoma in p53-deficient mice
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DOI：
10.1158/0008-5472.can-05-4609
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发表时间：
2006-07-01
期刊：
影响因子：
11.2
通讯作者：
DePinho, Ronald A.
中科院分区：
文献类型：
--
作者：
Farazi, Paraskevi A.;Zeisberg, Michael;DePinho, Ronald A.
肝内胆管细胞癌（CCA）是一种与p53突变、胆管损伤、炎症和纤维化相关的胆管上皮致命恶性肿瘤。在这里，为了验证CCA中的这些过程，我们开发了一种由慢性间歇性毒素暴露驱动的肝硬化模型，该模型引起胆管损伤/坏死和增殖，成纤维细胞募集和进行性细胞外基质（ECM）变化。基质微环境中的纤维化变化，以I型和III型胶原增加和成纤维细胞募集为代表，仅在携带p53突变等位基因的小鼠中显示刺激胆管上皮增生，随后进展为恶性肝内CCA。这些小鼠CCA具有人类肝内CCA的组织学和遗传学特征，包括致密瘤周纤维化、诱导型一氧化氮合酶、硝基酪氨酸和环氧合酶-2表达增加、c-Met激活、cErbB 2过表达、膜相关E-钙粘蛋白下调和p53密码子248突变。因此，p53缺陷、慢性胆管损伤/增殖和纤维化基质微环境协同诱导肝内CCA，突出了ECM微环境在这种常见肝癌中的关键作用。
Intrahepatic cholangiocarcinoma (CCA) is a lethal malignancy of the biliary epithelium associated with p53 mutations, bile duct injury, inflammation, and fibrosis. Here, to validate these processes in CCA, we developed a liver cirrhosis model driven by chronic intermittent toxin exposure, which provokes bile duct injury/necrosis and proliferation, fibroblast recruitment, and progressive extracellular matrix (ECM) changes. Fibrotic changes in the matrix microenvironment, typified by increased type I and III collagens and fibroblast recruitment, were shown to stimulate biliary epithelium hyperplasia with subsequent progression to malignant intrahepatic CCA only in mice harboring a p53 mutant allele. These murine CCAs bear histologic and genetic features of human intrahepatic CCA, including dense peritumoral fibrosis, increased inducible nitric oxide synthase, nitrotyrosine, and cyclooxygenase-2 expression, c-Met activation, cErbB2 overexpression, down-regulation of membrane-associated E-cadherin, and p53 codon 248 mutation. Thus, p53 deficiency, chronic bile duct injury/proliferation, and the fibrotic matrix microenvironment cooperate to induce intrahepatic CCA, highlighting the key role of the ECM microenvironment in this common liver cancer.