Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome, Italy.
Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.
Hepatology. 2019 Feb;69(2):622-638. doi: 10.1002/hep.30210. Epub 2019 Jan 4.
Primary sclerosing cholangitis (PSC) is a chronic inflammatory cholangiopathy frequently complicated by cholangiocarcinoma (CCA). Massive proliferation of biliary tree stem/progenitor cells (BTSCs), expansion of peribiliary glands (PBGs), and dysplasia were observed in PSC. The aims of the present study were to evaluate the involvement of PBGs and BTSCs in CCA which emerged in PSC patients. Specimens from normal liver (n = 5), PSC (n = 20), and PSC-associated CCA (n = 20) were included. Samples were processed for histology, immunohistochemistry, and immunofluorescence. In vitro experiments were performed on human BTSCs, human mucinous primary CCA cell cultures, and human cholangiocyte cell lines (H69). Our results indicated that all CCAs emerging in PSC patients were mucin-producing tumors characterized by PBG involvement and a high expression of stem/progenitor cell markers. Ducts with neoplastic lesions showed higher inflammation, wall thickness, and PBG activation compared to nonneoplastic PSC-affected ducts. CCA showed higher microvascular density and higher expression of nuclear factor kappa B, interleukin-6, interleukin-8, transforming growth factor β, and vascular endothelial growth factor-1 compared to nonneoplastic ducts. CCA cells were characterized by a higher expression of epithelial-to-mesenchymal transition (EMT) traits and by the absence of primary cilia compared to bile ducts and PBG cells in controls and patients with PSC. Our in vitro study demonstrated that lipopolysaccharide and oxysterols (PSC-related stressors) induced the expression of EMT traits, the nuclear factor kappa B pathway, autophagy, and the loss of primary cilia in human BTSCs. Conclusion: CCA arising in patients with PSC is characterized by extensive PBG involvement and by activation of the BTSC niche in these patients, the presence of duct lesions at different stages suggests a progressive tumorigenesis.
原发性硬化性胆管炎（PSC）是一种慢性炎症性胆管病，常伴有胆管癌（CCA）。在 PSC 中观察到胆管树干/祖细胞（BTSC）大量增殖、周边胆管腺（PBG）扩张和发育不良。本研究旨在评估 PSC 患者中出现的 CCA 中 PBG 和 BTSC 的参与情况。纳入了正常肝脏（n=5）、PSC（n=20）和 PSC 相关 CCA（n=20）的标本。对标本进行了组织学、免疫组织化学和免疫荧光分析。在人 BTSC、人黏液性原发性 CCA 细胞培养物和人胆管细胞系（H69）上进行了体外实验。我们的结果表明，所有在 PSC 患者中出现的 CCA 都是黏液产生肿瘤，其特征是 PBG 参与和干细胞/祖细胞标志物高表达。与非肿瘤性 PSC 受累胆管相比，具有肿瘤病变的胆管表现出更高的炎症、壁厚度和 PBG 激活。与非肿瘤性 PSC 受累胆管相比，CCA 显示出更高的微血管密度和更高的核因子 kappa B、白细胞介素-6、白细胞介素-8、转化生长因子-β和血管内皮生长因子-1 的表达。与对照组和 PSC 患者的胆管和 PBG 细胞相比，CCA 细胞表现出更高的上皮-间充质转化（EMT）特征表达，并且缺乏初级纤毛。我们的体外研究表明，脂多糖和氧化固醇（PSC 相关应激物）诱导人 BTSC 中 EMT 特征、核因子 kappa B 途径、自噬和初级纤毛丧失的表达。结论：PSC 患者中发生的 CCA 具有广泛的 PBG 参与和这些患者中 BTSC 龛的激活，不同阶段的胆管病变的存在提示进行性肿瘤发生。
