Zhao Jiangang, Schlößer Hans A, Wang Zhefang, Qin Jie, Li Jiahui, Popp Felix, Popp Marie Christine, Alakus Hakan, Chon Seung-Hun, Hansen Hinrich P, Neiss Wolfram F, Jauch Karl-Walter, Bruns Christiane J, Zhao Yue
Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany.
Department of General, Visceral und Vascular Surgery, Ludwig-Maximilian-University (LMU), 81377 Munich, Germany.
Cancers (Basel). 2019 Jun 22;11(6):874. doi: 10.3390/cancers11060874.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Tumor-derived extracellular vesicles (EVs) induce pre-metastatic niche formation to promote metastasis. We isolated EVs from a highly-metastatic pancreatic cancer cell line and patient-derived primary cancer cells by ultracentrifugation. The protein content of EVs was analyzed by mass spectrometry. The effects of PDAC-derived EVs on natural kill (NK) cells were investigated by flow cytometry. The serum EVs' TGF-β1 levels were quantified by ELISA. We found that integrins were enriched in PDAC-derived EVs. The expression of NKG2D, CD107a, TNF-α, and INF-γ in NK cells was significantly downregulated after co-culture with EVs. NK cells also exhibited decreased levels of CD71 and CD98, as well as impaired glucose uptake ability. In addition, NK cell cytotoxicity against pancreatic cancer stem cells was attenuated. Moreover, PDAC-derived EVs induced the phosphorylation of Smad2/3 in NK cells. Serum EVs' TGF-β1 was significantly increased in PDAC patients. Our findings emphasize the immunosuppressive role of PDAC-derived EVs and provide new insights into our understanding of NK cell dysfunction regarding pre-metastatic niche formation in PDAC.
胰腺导管腺癌（PDAC）是最致命的恶性肿瘤之一。肿瘤来源的细胞外囊泡（EVs）可诱导前转移微环境形成以促进转移。我们通过超速离心从高转移性胰腺癌细胞系和患者来源的原发性癌细胞中分离出EVs。通过质谱分析EVs的蛋白质含量。通过流式细胞术研究PDAC来源的EVs对自然杀伤（NK）细胞的影响。通过酶联免疫吸附测定（ELISA）对血清EVs中的转化生长因子-β1（TGF-β1）水平进行定量。我们发现整合素在PDAC来源的EVs中富集。与EVs共培养后，NK细胞中NKG2D、CD107a、肿瘤坏死因子-α（TNF-α）和干扰素-γ（INF-γ）的表达显著下调。NK细胞还表现出CD71和CD98水平降低，以及葡萄糖摄取能力受损。此外，NK细胞对胰腺癌干细胞的细胞毒性减弱。此外，PDAC来源的EVs诱导NK细胞中Smad2/3磷酸化。PDAC患者血清EVs中的TGF-β1显著升高。我们的研究结果强调了PDAC来源的EVs的免疫抑制作用，并为我们理解PDAC中前转移微环境形成过程中NK细胞功能障碍提供了新的见解。
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