Fibroblast-Derived Extracellular Vesicles Induce Lung Cancer Progression in the IPF Microenvironment
Fibroblast-Derived Extracellular Vesicles Induce Lung Cancer Progression in the IPF Microenvironment
复制标题
成纤维细胞衍生的细胞外囊泡在 IPF 微环境中诱导肺癌进展
DOI：
10.1165/rcmb.2022-0253oc
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发表时间：
2023
影响因子：
6.4
通讯作者：
Kuwano Kazuyoshi
中科院分区：
文献类型：
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作者：
Fujita Yu;Fujimoto Shota;Miyamoto Atsushi;Kaneko Reika;Kadota Tsukasa;Watanabe Naoaki;Kizawa Ryusuke;Kawamoto Hironori;Watanabe Junko;Utsumi Hirofumi;Wakui Hiroshi;Minagawa Shunsuke;Araya Jun;Ohtsuka Takashi;Ochiya Takahiro;Kuwano Kazuyoshi
特发性肺纤维化（IPF）是一种与肺癌风险增加相关的进行性衰老相关肺部疾病。尽管先前的研究表明IPF延长了肺癌患者的生存期，但IPF是否独立影响癌症恶性程度和预后仍无定论。细胞外囊泡（EVs）是近年来发现的一种分子生物标志物的活性载体，也是肺内环境稳定和发病机制中细胞间通讯的介质。EV cargo介导的成纤维细胞-肿瘤细胞通讯可能通过调节多种信号通路参与肺癌的发生和发展。在这项研究中，我们研究了肺成纤维细胞（LF）衍生的EV对IPF微环境中非小细胞肺癌（NSCLC）恶性肿瘤的影响。在这里，我们发现来自IPF患者的LF具有肌成纤维细胞分化和细胞衰老的表型。此外，我们发现IPF LF衍生的EV具有显著改变的microRNA组成，并对NSCLC细胞发挥促增殖功能。从机制上讲，表型主要归因于miR-19 a在IPF LF衍生EV中的富集。作为下游信号通路，IPF LF衍生EV中的mir-19 a调节NSCLC中ZMYND 11介导的c-Myc激活，可能导致NSCLC伴IPF患者的预后不良。我们的发现为理解IPF微环境中的肺癌进展提供了新的机制见解。因此，阻断IPF LF衍生的EV miR-19 a的分泌及其信号传导途径是管理IPF和肺癌进展的潜在治疗策略。
Idiopathic pulmonary fibrosis (IPF) is a progressive aging-related lung disease associated with increased lung cancer risk. Although previous studies have shown that IPF worsens the survival of patients with lung cancer, whether IPF independently affects cancer malignancy and prognosis remains inconclusive. Extracellular vesicles (EVs) have recently emerged as active carriers of molecular biomarkers and mediators of intercellular communication in lung homeostasis and pathogenesis. EV cargo-mediated fibroblast–tumor cell communication might participate in the development and progression of lung cancer by modulating various signaling pathways. In this study, we examined the impact of lung fibroblast (LF)-derived EVs on non-small cell lung cancer (NSCLC) malignancy in the IPF microenvironment. Here, we showed that LFs derived from patients with IPF have phenotypes of myofibroblast differentiation and cellular senescence. Furthermore, we found that IPF LF-derived EVs have markedly altered microRNA compositions and exert proproliferative functions on NSCLC cells. Mechanistically, the phenotype was attributed mainly to the enrichment of miR-19a in IPF LF-derived EVs. As a downstream signaling pathway, mir-19a in IPF LF-derived EVs regulates ZMYND11-mediated c-Myc activation in NSCLC, potentially contributing to the poor prognosis of patients with NSCLC with IPF. Our discoveries provide novel mechanistic insights for understanding lung cancer progression in the IPF microenvironment. Accordingly, blocking the secretion of IPF LF-derived EV miR-19a and their signaling pathways is a potential therapeutic strategy for managing IPF and lung cancer progression.