Background: LUAD, the most common subtype of lung cancer, particularly in non-smokers, is significantly influenced by air pollution from fine particulate matter (PM). One suspected method by which PM contributes to cancer progression is through angiogenesis, which promotes tumor growth and metastasis. This study was conducted to explore the impact of long-term PM exposure on the progression of LUAD, focusing on angiogenesis promotion. Methods: We conducted an integrative bioinformatics analysis incorporating epidemiological and transcriptomic datasets from public repositories (TCGA and GEO) to evaluate differential VEGFA expression in LUAD tissues and its relationship to regional PM exposure. In vitro and in vivo assays using PM-adapted NSCLC cell lines and murine xenograft models served as secondary confirmatory experiments supporting the computational results. Results: Epidemiological analysis revealed a strong positive correlation between long-term PM exposure and lung adenocarcinoma mortality across U.S. states (r = 0.7638,p< 0.0001), underscoring a population-level impact. Bioinformatics analysis identified a significant upregulation of VEGFA in NSCLC tumors from regions with high PM levels, with VEGFA overexpression also associated with poorer patient survival. Gene ontology and pathway enrichment analyses implicated angiogenesis-related processes. These findings were supported by experimental models, in which long-term PM exposure on human and murine LUAD cell lines (A549, H1299, and LLC) induced VEGFA and p-ERK overexpression. Furthermore, PM-exposed cells enhanced angiogenesis processes, as evidenced by increased endothelial cell tube formation and migration in vitro, and promoted tumor vascularization in a xenograft model. These pro-angiogenesis effects were abrogated following inhibition of the MAPK signaling pathway or blockade of VEGFA. Conclusions: Our findings reveal a compelling molecular link between PM exposure and NSCLC progression, centered on VEGFA-driven angiogenesis and urging the need to reduce ambient PM exposure to mitigate its oncogenic impact.
背景：肺腺癌（LUAD）作为肺癌最常见的亚型，尤其在非吸烟者中，其发生发展受到细颗粒物（PM）空气污染的显著影响。PM促进癌症进展的潜在机制之一是通过血管生成，从而加速肿瘤生长与转移。本研究旨在探讨长期PM暴露对LUAD进展的影响，重点关注其对血管生成的促进作用。 方法：我们整合了公共数据库（TCGA与GEO）中的流行病学与转录组学数据集进行生物信息学分析，评估LUAD组织中VEGFA表达的差异及其与区域PM暴露水平的关系。同时，采用经PM长期暴露处理的人非小细胞肺癌（NSCLC）细胞系及小鼠异种移植模型进行体外与体内实验，作为支持计算结果的验证性研究。 结果：流行病学分析显示，美国各州长期PM暴露水平与肺腺癌死亡率呈显著正相关（r = 0.7638, p < 0.0001），揭示了PM在人群层面的影响。生物信息学分析发现，高PM水平地区NSCLC肿瘤组织中VEGFA表达显著上调，且VEGFA过表达与患者不良预后相关。基因本体与通路富集分析提示该过程涉及血管生成相关通路。实验模型进一步验证了这些发现：长期PM暴露可诱导人源与鼠源LUAD细胞系（A549、H1299及LLC）中VEGFA及p-ERK表达上调。此外，PM暴露细胞在体外实验中表现出促进内皮细胞成管与迁移的能力，并在异种移植模型中加速肿瘤血管生成。这些促血管生成效应在抑制MAPK信号通路或阻断VEGFA后被消除。 结论：本研究揭示了PM暴露与NSCLC进展之间的关键分子联系，其核心机制为VEGFA驱动的血管生成过程，强调了降低环境PM暴露对减轻其致癌影响的紧迫性。
肿瘤(癌症)患者之家