Pham-Danis Catherine, Chia Shi B, Scarborough Hannah A, Danis Etienne, Nemkov Travis, Zaberezhnyy Vadym, Christenson Jessica L, Kleczko Emily K, Navarro Andre, Goodspeed Andrew, Bonney Elizabeth A, Dinarello Charles A, Marchetti Carlo, Nemenoff Raphael A, Hansen Kirk C, DeGregori James
Department of Biochemistry and Molecular Genetics University of Colorado Anschutz Medical Campus Aurora Colorado USA.
Department of Biomedical Informatics University of Colorado Anschutz Medical Campus University of Colorado Cancer Center Aurora Colorado USA.
Aging Cancer. 2025 Mar;6(1):3-18. doi: 10.1002/aac2.12077. Epub 2024 Oct 30.
Lung cancer is the leading cause of cancer death in the world. While cigarette smoking is the major preventable factor for cancers in general and lung cancer in particular, old age is also a major risk factor. Aging-related chronic, low-level inflammation, termed inflammaging, has been widely documented; however, it remains unclear how inflammaging contributes to increased lung cancer incidence.
The aim of this study was to establish connections between aging-associated changes in the lungs and cancer risk.
We analyzed public databases of gene expression for normal and cancerous human lungs and used mouse models to understand which changes were dependent on inflammation, as well as to assess the impact on oncogenesis.
Analyses of GTEx and TCGA databases comparing gene expression profiles from normal lungs, lung adenocarcinoma, and lung squamous cell carcinoma of subjects across age groups revealed upregulated pathways such as inflammatory response, TNFA signaling via NFκB, and interferon-gamma response. Similar pathways were identified comparing the gene expression profiles of young and old mouse lungs. Transgenic expression of alpha 1 antitrypsin (AAT) partially reverses increases in markers of aging-associated inflammation and immune deregulation. Using an orthotopic model of lung cancer using cells derived from EML4-ALK fusion-induced adenomas, we demonstrated an increased tumor outgrowth in lungs of old mice while NLRP3 knockout in old mice decreased tumor volumes, suggesting that inflammation contributes to increased lung cancer development in aging organisms.
These studies reveal how expression of an anti-inflammatory mediator (AAT) can reduce some but not all aging-associated changes in mRNA and protein expression in the lungs. We further show that aging is associated with increased tumor outgrowth in the lungs, which may relate to an increased inflammatory microenvironment.
肺癌是全球癌症死亡的主要原因。虽然吸烟是一般癌症尤其是肺癌的主要可预防因素，但老年也是一个主要风险因素。与衰老相关的慢性低度炎症，即炎性衰老，已被广泛记录；然而，炎性衰老如何导致肺癌发病率增加仍不清楚。
本研究的目的是建立肺部与衰老相关变化和癌症风险之间的联系。
我们分析了正常和癌性人肺的基因表达公共数据库，并使用小鼠模型来了解哪些变化依赖于炎症，以及评估其对肿瘤发生的影响。
对GTEx和TCGA数据库进行分析，比较不同年龄组受试者的正常肺、肺腺癌和肺鳞状细胞癌的基因表达谱，发现炎症反应、通过NFκB的TNFA信号传导和干扰素-γ反应等通路上调。比较年轻和老年小鼠肺的基因表达谱也发现了类似的通路。α1抗胰蛋白酶（AAT）的转基因表达部分逆转了衰老相关炎症和免疫失调标志物的增加。使用源自EML4-ALK融合诱导腺瘤的细胞建立肺癌原位模型，我们证明老年小鼠肺中的肿瘤生长增加，而老年小鼠中的NLRP3基因敲除减少了肿瘤体积，这表明炎症促进了衰老生物体中肺癌的发展。
这些研究揭示了抗炎介质（AAT）的表达如何减少肺部mRNA和蛋白质表达中一些但不是所有与衰老相关的变化。我们进一步表明，衰老与肺肿瘤生长增加有关，这可能与炎症微环境增加有关。
