Watabe Shiori, Kikuchi Yoshinao, Morita Shigeki, Komura Daisuke, Numakura Satoe, Kumagai-Togashi Arisa, Watanabe Masato, Matsutani Noriyuki, Kawamura Masafumi, Yasuda Masanori, Uozaki Hiroshi
Department of Pathology, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.
Department of Pathology, Saitama Medical University International Medical Center, Hidaka-City, Tokyo, Japan.
Cancer Med. 2020 Apr;9(8):2879-2890. doi: 10.1002/cam4.2928. Epub 2020 Feb 24.
Pre-resection pleural lavage cytology is useful to predict tumor recurrence and the prognosis of lung cancer patients. Recently, extracellular vesicles (EVs) isolated from effusion specimens have come under the spotlight, and several studies showed that microRNA in EVs is associated with prognosis. MicroRNA-21 (miR-21) is a representative onco-microRNA, and miR-21 in EVs (EV-miR-21) promotes cancer dissemination by inducing mesothelial to mesenchymal transition (MMT) in the peritoneal cavity. In this study, we isolated EVs from pleural lavage fluid and focused on EV-miR-21 as a diagnostic factor with a relationship to pleural dissemination.
The Cancer Genome Atlas dataset comprising of 448 cases of lung adenocarcinoma, tissue microarray of 144 cases of lung adenocarcinoma, and pleural lavage fluid of 41 cases was used to examine miR-21 expression levels. The function of EV-miR-21 was investigated in vitro.
The miR-21 expression level in primary sites was associated with a poor prognosis and correlated with pleural invasion of adenocarcinoma. EV-miR-21 levels in pleural lavage fluid were associated with positive cytology and pleural invasion in the primary sites, even in cytology-negative cases. In vitro studies demonstrated that EV-miR-21 induces the MMT. Mesothelial cells in the MMT showed functions similar to cancer-associated fibroblasts, which are an important stromal component in primary sites and disseminated pleural lesions.
EV-miR-21 in pleural lavage fluid is important as a diagnostic and prognostic factor. Moreover, EV-miR-21 induces the MMT, which can form premetastatic niches of dissemination in the pleural cavity.
术前胸腔灌洗细胞学检查有助于预测肺癌患者的肿瘤复发及预后。近来，从积液标本中分离出的细胞外囊泡（EVs）受到关注，多项研究表明EVs中的微小RNA与预后相关。微小RNA-21（miR-21）是一种典型的致癌微小RNA，EVs中的miR-21（EV-miR-21）通过诱导腹膜间皮向间充质转化（MMT）促进癌症播散。在本研究中，我们从胸腔灌洗液中分离出EVs，并将EV-miR-21作为与胸膜播散相关的诊断因子进行研究。
使用包含448例肺腺癌病例的癌症基因组图谱数据集、144例肺腺癌组织芯片以及41例胸腔灌洗液来检测miR-21的表达水平。在体外研究EV-miR-21 的功能。
原发部位的miR-21表达水平与预后不良相关，且与腺癌的胸膜侵犯相关。胸腔灌洗液中的EV-miR-21水平与原发部位细胞学阳性及胸膜侵犯相关，即使在细胞学阴性的病例中也是如此。体外研究表明，EV-miR-21可诱导MMT。MMT中的间皮细胞表现出与癌症相关成纤维细胞相似的功能，而癌症相关成纤维细胞是原发部位和胸膜播散性病变中的重要基质成分。
胸腔灌洗液中的EV-miR-21作为诊断和预后因子具有重要意义。此外，EV-miR-21可诱导MMT，这可在胸腔中形成播散性的前转移微环境。
