Intrapleural Adenoviral-mediated Endothelial Cell Protein C Receptor Gene Transfer Suppresses the Progression of Malignant Pleural Mesothelioma in a Mouse Model.
Intrapleural Adenoviral-mediated Endothelial Cell Protein C Receptor Gene Transfer Suppresses the Progression of Malignant Pleural Mesothelioma in a Mouse Model.
复制标题
胸膜内腺病毒介导的内皮细胞蛋白 C 受体基因转移抑制小鼠模型中恶性胸膜间皮瘤的进展。
DOI：
10.1038/srep36829
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发表时间：
2016
影响因子：
4.6
通讯作者：
Pendurthi,UshaR
中科院分区：
文献类型：
--
作者：
Keshava,Shiva;Rao,LVijayaMohan;Pendurthi,UshaR
恶性胸膜间皮瘤（MPM）是一种侵袭性胸部癌症，由于对标准治疗干预措施反应不佳，死亡率很高。我们最近的研究表明，MPM 细胞中内皮细胞蛋白 C 受体 (EPCR) 的表达可抑制致瘤性。本研究旨在探讨EPCR抑制MPM肿瘤生长的机制，并评估EPCR基因治疗是否可以在MPM小鼠模型中抑制MPM的进展。胸腔灌洗液细胞因子测定结果显示，与植入缺乏 EPCR 的 MPM 细胞的小鼠相比，植入表达 EPCR 的 MPM 细胞的小鼠体内 IFNγ 和 TNFα 水平升高。体外研究表明，EPCR 表达使 MPM 细胞对 IFNγ + TNFα 诱导的细胞凋亡高度敏感。将 Ad.EPCR 胸膜内注射到具有源自缺乏 EPCR 的 MPM 细胞的已建立 MPM 的小鼠中，可减少肿瘤生长的进展。 Ad.EPCR 治疗引起巨噬细胞和 NK 细胞募集到肿瘤微环境中，并增加胸膜腔中 IFNγ 和 TNFα 的水平。 Ad.EPCR 处理导致肿瘤细胞凋亡显着增加。总之，我们的数据表明 MPM 细胞中 EPCR 表达促进肿瘤细胞凋亡，胸腔内 EPCR 基因治疗抑制 MPM 进展。
Malignant pleural mesothelioma (MPM) is an aggressive thoracic cancer with a high mortality rate as it responds poorly to standard therapeutic interventions. Our recent studies showed that expression of endothelial cell protein C receptor (EPCR) in MPM cells suppresses tumorigenicity. The present study was aimed to investigate the mechanism by which EPCR suppresses MPM tumor growth and evaluate whether EPCR gene therapy could suppress the progression of MPM in a mouse model of MPM. Measurement of cytokines from the pleural lavage showed that mice implanted with MPM cells expressing EPCR had elevated levels of IFNγ and TNFα compared to mice implanted with MPM cells lacking EPCR.In vitrostudies demonstrated that EPCR expression renders MPM cells highly susceptible to IFNγ + TNFα-induced apoptosis. Intrapleural injection of Ad.EPCR into mice with an established MPM originating from MPM cells lacking EPCR reduced the progression of tumor growth. Ad.EPCR treatment elicited recruitment of macrophages and NK cells into the tumor microenvironment and increased IFNγ and TNFα levels in the pleural space. Ad.EPCR treatment resulted in a marked increase in tumor cell apoptosis. In summary, our data show that EPCR expression in MPM cells promotes tumor cell apoptosis, and intrapleural EPCR gene therapy suppresses MPM progression.