Epigenomics and biomarkers of solid tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
Thoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
Cell Death Dis. 2023 Oct 14;14(10):681. doi: 10.1038/s41419-023-06212-1.
Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer development. COPD induces activation of hypoxia-induced signaling, causing remodeling of surrounding microenvironmental cells also modulating the release and cargo of their extracellular vesicles (EVs). We aimed to evaluate the potential role of circulating EVs from COPD subjects in lung cancer onset. Plasma-EVs were isolated by ultracentrifugation from heavy smoker volunteers with (COPD-EVs) or without (heavy smoker-EVs, HS-EV) COPD and characterized following MISEV guidelines. Immortalized human bronchial epithelial cells (CDK4, hTERT-HBEC3-KT), genetically modified with different oncogenic alterations commonly found in lung cancer (sh-p53, KRAS), were used to test plasma-EVs pro-tumorigenic activity in vitro. COPD-EVs mainly derived from immune and endothelial cells. COPD-EVs selectively increased the subset of CD133CXCR4 metastasis initiating cells (MICs) in HBEC-sh-p53-KRAS cells and stimulated 3D growth, migration/invasion, and acquisition of mesenchymal traits. These effects were not observed in HBEC cells bearing single oncogenic mutation (sh-p53 or KRASV12). Mechanistically, hypoxia-inducible factor 1-alpha (HIF-1α) transferred from COPD-EVs triggers CXCR4 pathway activation that in turn mediates MICs expansion and acquisition of pro-tumorigenic effects. Indeed, HIF-1α inhibition or CXCR4 silencing prevented the acquisition of malignant traits induced by COPD-EVs alone. Hypoxia recapitulates the effects observed with COPD-EVs in HBEC-sh-p53-KRAS cells. Notably, higher levels of HIF-1α were observed in EVs from COPD subjects who subsequently developed cancer compared to those who remained cancer-free. Our findings support a role of COPD-EVs to promote the expansion of MICs in premalignant epithelial cells through HIF-1α-CXCR4 axis activation thereby potentially sustaining lung cancer progression.
慢性阻塞性肺疾病（COPD）是肺癌发展的一个风险因素。COPD 诱导缺氧诱导信号的激活，导致周围微环境细胞的重塑，也调节其细胞外囊泡（EVs）的释放和货物。我们旨在评估 COPD 患者循环 EVs 在肺癌发病中的潜在作用。通过超速离心从有（COPD-EVs）或没有（重度吸烟者-EVs，HS-EV）COPD 的重度吸烟者志愿者的血浆中分离出 EVs，并按照 MISEV 指南进行特征描述。使用不同的致癌改变遗传修饰的永生化人支气管上皮细胞（CDK4，hTERT-HBEC3-KT），这些改变常见于肺癌（sh-p53，KRAS），用于体外测试血浆-EVs 的促肿瘤活性。COPD-EVs 主要来源于免疫细胞和内皮细胞。COPD-EVs 选择性地增加了 HBEC-sh-p53-KRAS 细胞中 CD133CXCR4 转移起始细胞（MICs）的亚群，并刺激 3D 生长、迁移/侵袭和获得间充质特征。在携带单个致癌突变（sh-p53 或 KRASV12）的 HBEC 细胞中没有观察到这些效应。在机制上，从 COPD-EVs 中转移的缺氧诱导因子 1-α（HIF-1α）触发 CXCR4 途径的激活，进而介导 MICs 的扩增和获得促肿瘤发生的效应。事实上，HIF-1α 抑制或 CXCR4 沉默阻止了 COPD-EVs 单独诱导的恶性特征的获得。缺氧再现了在 HBEC-sh-p53-KRAS 细胞中观察到的 COPD-EVs 引起的效应。值得注意的是，与未患癌症的 COPD 患者相比，随后发生癌症的 COPD 患者的 EVs 中观察到更高水平的 HIF-1α。我们的研究结果支持 COPD-EVs 通过 HIF-1α-CXCR4 轴的激活促进癌前上皮细胞中 MICs 的扩增，从而可能维持肺癌的进展。
