Carcinogenic Liver Fluke Secretes Extracellular Vesicles That Promote Cholangiocytes to Adopt a Tumorigenic Phenotype.
Carcinogenic Liver Fluke Secretes Extracellular Vesicles That Promote Cholangiocytes to Adopt a Tumorigenic Phenotype.
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DOI：
10.1093/infdis/jiv291
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发表时间：
2015-11-15
期刊：
影响因子：
--
通讯作者：
Loukas A
中科院分区：
文献类型：
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作者：
Chaiyadet S;Sotillo J;Smout M;Cantacessi C;Jones MK;Johnson MS;Turnbull L;Whitchurch CB;Potriquet J;Laohaviroj M;Mulvenna J;Brindley PJ;Bethony JM;Laha T;Sripa B;Loukas A
背景。 在整个亚洲，胆管癌与肝吸虫 Opisthorchis viverrini 感染之间存在着前所未有的联系。多种过程，包括慢性炎症和寄生虫蛋白分泌到胆管上皮中，导致感染发展为癌症。迄今为止，寄生虫蛋白进入胆管细胞的机制和影响尚不清楚。方法。 使用各种显微镜技术来鉴定 O. viverrini 细胞外囊泡 (EV) 及其被人类胆管细胞的内化。使用质谱分析法，我们对 EV 蛋白质组和摄取 EV 后胆管细胞的相关变化进行了表征，并在受感染的仓鼠和人类的胆汁中检测到了 EV 蛋白。测量胆管细胞增殖和白细胞介素 6 (IL-6) 分泌，以评估 EV 内化的影响。结果。 在吸虫培养基和受感染宿主的胆汁样本中发现了 EV。胆管细胞内化的 EV 驱动细胞增殖和 IL-6 分泌，并诱导与内吞作用、伤口修复和癌症相关的蛋白质表达变化。 O. viverrini tetraspanin 抗体可阻断胆管细胞对 EV 的摄取和 IL-6 的分泌。结论。 这是首次在宿主组织中鉴定出来自多细胞病原体的 EV。我们的研究结果暗示了 O. viverrini EV 在发病机制中的作用，并强调了这种传染性癌症的疫苗开发方法。
Background. Throughout Asia, there is an unprecedented link between cholangiocarcinoma and infection with the liver fluke Opisthorchis viverrini. Multiple processes, including chronic inflammation and secretion of parasite proteins into the biliary epithelium, drive infection toward cancer. Until now, the mechanism and effects of parasite protein entry into cholangiocytes was unknown. Methods. Various microscopy techniques were used to identify O. viverrini extracellular vesicles (EVs) and their internalization by human cholangiocytes. Using mass spectrometry we characterized the EV proteome and associated changes in cholangiocytes after EV uptake, and we detected EV proteins in bile of infected hamsters and humans. Cholangiocyte proliferation and interleukin 6 (IL-6) secretion was measured to assess the impact of EV internalization. Results. EVs were identified in fluke culture medium and bile specimens from infected hosts. EVs internalized by cholangiocytes drove cell proliferation and IL-6 secretion and induced changes in protein expression associated with endocytosis, wound repair, and cancer. Antibodies to an O. viverrini tetraspanin blocked EV uptake and IL-6 secretion by cholangiocytes. Conclusions. This is the first time that EVs from a multicellular pathogen have been identified in host tissues. Our findings imply a role for O. viverrini EVs in pathogenesis and highlight an approach to vaccine development for this infectious cancer.