Inflammation Promotes Aging-Associated Oncogenesis in the Lung

Catherine Pham-Danis, Shi B. Chia, Hannah A. Scarborough, Etienne Danis, Travis Nemkov, Vadym Zaberezhnyy, Jessica L. Christenson, Emily K. Kleczko, Andre Navarro, Andrew Goodspeed, Elizabeth A. Bonney, Charles A. Dinarello, Carlo Marchetti, Raphael A. Nemenoff, Kirk C. Hansen, James DeGregori
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Abstract

Background

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.

Aim

The aim of this study was to establish connections between aging-associated changes in the lungs and cancer risk.

Methods

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.

Results

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.

Conclusions

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.

Abstract Image

炎症促进肺部衰老相关肿瘤的发生
肺癌是世界上癌症死亡的主要原因。虽然吸烟是导致癌症尤其是肺癌的主要可预防因素,但年老也是一个主要的危险因素。与衰老相关的慢性低水平炎症,被称为炎症,已被广泛记录;然而,目前尚不清楚炎症是如何导致肺癌发病率增加的。这项研究的目的是建立与年龄相关的肺部变化与癌症风险之间的联系。方法我们分析了正常和癌变人类肺部基因表达的公共数据库,并使用小鼠模型来了解哪些变化依赖于炎症,并评估对肿瘤发生的影响。结果GTEx和TCGA数据库比较了不同年龄组的正常肺、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。通过比较年轻和年老小鼠肺的基因表达谱,发现了类似的途径。α 1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。利用EML4-ALK融合诱导的腺瘤细胞建立肺癌原位模型,我们发现老年小鼠肺部肿瘤生长增加,而NLRP3基因敲除使老年小鼠的肿瘤体积减少,这表明炎症有助于增加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和蛋白表达的部分(但不是全部)衰老相关变化。我们进一步表明,衰老与肺部肿瘤生长增加有关,这可能与炎症微环境增加有关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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