Wei Mingtian, Yang Tinghan, Chen Xiangzheng, Wu Yangping, Deng Xiangbing, He Wanbin, Yang Jinliang, Wang Ziqiang
Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
Oncotarget. 2017 Jun 27;8(26):42262-42271. doi: 10.18632/oncotarget.15040.
Malignant ascites-derived exosomes have been demonstrated to participate in tumor metastasis. In peritoneal metastasis, normal mesothelial cells (MCs) can be converted into carcinoma-associated fibroblasts (CAFs) by mesothelial-mesenchymal transition (MMT). Herein, we evaluated the effect of malignant ascites-derived exosomes on peritoneal MCs in vitro and in vivo experiments to determine whether exosomes could educate MCs and contribute to peritoneal metastasis.Under the treatment of ascites-derived exosomes, peritoneal MCs showed increased ability to proliferate and migrate. Expression of CAFs specific proteins markers in MCs, including fibroblast activation protein (FAP), alpha-smooth muscle actin (α-SMA), and fibronectin, were increased after treatment of exosomes. In clinical samples test, TGF-β1 was found to be overexpressed in both malignant ascites and malignant ascites-derived exosomes, and the high volume of TGF-β1 may be responsible for peritoneum fibrosis. In addition, exosomes can increase xenograft tumor growth by suppressing the inhibitive ability on tumor cells by MCs. Besides, CAFs specific proteins markers including FAP, α-SMA, and vimentin were increased in clinical peritoneal biopsies. The immunohistochemical staining for mice tumor biopsies also revealed increased expression of fibronectin and FAP, along with decreased expression of E-cadherin and VCAM-1 after exosomes treatment.Thus, malignant ascites-derived exosomes may be of importance in the development of peritoneal metastasis by facilitating MCs to proliferate and convert into CAFs by TGF-β1 induced MMT.
恶性腹水来源的外泌体已被证明参与肿瘤转移。在腹膜转移中，正常间皮细胞（MCs）可通过间皮-间质转化（MMT）转化为癌相关成纤维细胞（CAFs）。在此，我们在体外和体内实验中评估了恶性腹水来源的外泌体对腹膜MCs的影响，以确定外泌体是否能影响MCs并促进腹膜转移。在腹水来源的外泌体处理下，腹膜MCs的增殖和迁移能力增强。外泌体处理后，MCs中CAFs特异性蛋白标志物的表达增加，包括成纤维细胞活化蛋白（FAP）、α平滑肌肌动蛋白（α-SMA）和纤连蛋白。在临床样本检测中，发现转化生长因子-β1（TGF-β1）在恶性腹水和恶性腹水来源的外泌体中均过表达，高含量的TGF-β1可能是腹膜纤维化的原因。此外，外泌体可通过抑制MCs对肿瘤细胞的抑制能力来促进异种移植肿瘤生长。此外，临床腹膜活检中CAFs特异性蛋白标志物包括FAP、α-SMA和波形蛋白增加。小鼠肿瘤活检的免疫组织化学染色也显示，外泌体处理后纤连蛋白和FAP表达增加，而E-钙黏蛋白和血管细胞黏附分子-1（VCAM-1）表达降低。因此，恶性腹水来源的外泌体可能通过促进MCs增殖并通过TGF-β1诱导的MMT转化为CAFs，在腹膜转移的发生发展中起重要作用。
