Chemoresistance Transmission via Exosome-Mediated EphA2 Transfer in Pancreatic Cancer
Chemoresistance Transmission via Exosome-Mediated EphA2 Transfer in Pancreatic Cancer
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DOI：
10.7150/thno.26650
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发表时间：
2018-01-01
期刊：
影响因子：
12.4
通讯作者：
Hu, Ye
中科院分区：
文献类型：
--
作者：
Fan, Jia;Wei, Qian;Hu, Ye
基本原理：外泌体是由血液和其他体液中发现的大多数细胞分泌的小的细胞外囊泡，并且其含有对应于其来源细胞类型的细胞质物质和膜因子。外泌体膜因子和内容物已被报道在多项研究中改变邻近和远处细胞的行为，但癌症来源的外泌体对化疗耐药性的影响尚不清楚。方法：从三个胰腺癌（PC）细胞系分离的外泌体显示可变吉西他滨（GEM）抗性（PANC-1，MIA PaCa-2和BxPC-3）进行了测试，以确定它们在这些细胞系中传递化疗耐药性的能力。进行比较蛋白质组学以鉴定赋予化学抗性的关键外泌体蛋白。在用重组Ephrin A型受体2（EphA 2）（候选的化学抗性转移因子）处理的GEM应答PC细胞系中，或来自用或不用EphA 2 shRNA处理的化学抗性PC细胞系的外泌体中，评估细胞存活率。比较蛋白质组学确定PANC-1外泌体相对于较低化学抗性PC细胞系MIA PaCa-2和BxPC-3的外泌体过表达Ephrin A型受体2（EphA 2）。PANC-1细胞中的EphA 2敲低抑制了它们将外来体介导的化学抗性传递给MIA PaCa-2和BxPC-3的能力，而用可溶性EphA 2处理MIA PaCa-2和BxPC-3细胞不促进化学抗性，表明膜携带的EphA 2对于EphA 2化学抗性效应是重要的。外泌体EphA 2表达可以传递化疗耐药性，并可能作为PC治疗反应的微创预测生物标志物。进一步的工作应该解决额外的外泌体因子是否调节对PC或其他癌症类型的其他癌症治疗剂的抗性。
Rationale: Exosomes are small extracellular vesicles secreted by most cells that are found in blood and other bodily fluids, and which contain cytoplasmic material and membrane factors corresponding to their cell type of origin. Exosome membrane factors and contents have been reported to alter adjacent and distant cell behavior in multiple studies, but the impact of cancer-derived exosomes on chemoresistance is less clear.Methods: Exosomes isolated from three pancreatic cancer (PC) cell lines displaying variable gemcitabine (GEM) resistance (PANC-1, MIA PaCa-2, and BxPC-3) were tested for their capacity to transmit chemoresistance among these cell lines. Comparative proteomics was performed to identify key exosomal proteins that conferred chemoresistance. Cell survival was assessed in GEM responsive PC cell lines treated with recombinant Ephrin type-A receptor 2 (EphA2), a candidate chemoresistance transfer factor, or exosomes from a chemoresistant PC cell line treated with or without EphA2 shRNA.Results: Exosomes from chemoresistant PANC-1 cells increased the GEM resistance of MIA PaCa-2 and BxPC-3 cell cultures. Comparative proteomics determined that PANC-1 exosomes overexpressed Ephrin type-A receptor 2 (EphA2) versus exosomes of less chemoresistant PC cell lines MIA PaCa-2 and BxPC-3. EphA2-knockdown in PANC-1 cells inhibited their ability to transmit exosome-mediated chemoresistance to MIA PaCa-2 and BxPC-3, while treatment of MIA PaCa-2 and BxPC-3 cells with soluble EphA2 did not promote chemoresistance, indicating that membrane carried EphA2 was important for the EphA2 chemoresistance effect.Conclusion: Exosomal EphA2 expression could transmit chemoresistance and may potentially serve as a minimally-invasive predictive biomarker for PC treatment response. Further work should address whether additional exosomal factors regulate resistance to other cancer therapeutic agents for PC or other cancer types.