利用PDX模型研究PM2.5对不同亚型肺癌发展和转移的影响及其机制

The morbidity and the mortality of lung cancer is higher than that of other tumors in China. In our clinical works, we find that the constitution of lung cancer has changed significantly and the female cases and the adenocarcinoma cases in lung cancer increase every year. What caused these changes? What role does the environment factor,especially the PM2.5, play in this process? To understand the effect of small particles in air on health, this project will first study the clinical characters of lung cancer patients from different regions, which were polluted badly, and interpret the relationship between air pollution and lung cancer development. Then we will illuminate the effects of PM2.5 on the germination, development and metastasis of different pathological types of lung cancer using patient-derived xenografts (PDX) animals and primary lung cancer cells. PDX animal is made by engrafting the tumor tissues from patient into the immune-deficient mouse and it maintains the characters of the original tumor mostly and is widely used in tumor studies. We will also discuss the effects of PM2.5 on lung cancer cells by using air-liquid cell exposure model which is close to the real process of human exposure to air contaminants. Finally the distribution of PM2.5 in lung cancer cells and in PDX animals and the interaction between particles and the cell organelles are also the important parts that we will find. The results of this study will provide some useful information to prevent and control the bad effects of air pollution on human health.

肺癌是我国增长幅度最大、危害最严重的恶性肿瘤。目前肺癌的病理类型构成比发生了明显的改变，腺癌比例逐年上升。大气污染是普遍和主要的环境致癌物，大气细颗粒物污染在肺癌构成比变化中的作用如何？本项目以北京和石家庄等城市的肺癌患者为研究对象，重点研究空气污染对肺癌发生的影响，通过基因组学和蛋白质组学等技术，寻找与空气污染相关的预测标志物；利用最大程度保留临床肺癌患者肿瘤分子、遗传和异质性特点的PDX动物模型和临床肺癌患者肿瘤原代细胞，拟探究不同地域来源的PM2.5对不同亚型肺癌发生、发展及转移的影响及其分子机制；利用贴近真实情况的气液界面细胞暴露模型，在接近人真实暴露水平上，寻找不同地域PM2.5对不同亚型肺癌的发生、发展和转移影响的生物学相关机制。该项目的研究结果有利于为大气颗粒物不良效应的预防和控制策略提供科学依据。

肺癌是世界范围内最常见的恶性肿瘤之一，是造成我国肿瘤患者死亡的首要病因，其中肺腺癌的发病率癌呈上升趋势。作为普遍和主要的环境致癌物，大气污染已经引起了公众的广泛关注，大气污染成因复杂，研究大气细/超细颗粒物毒性组分对肺癌发展和转移的影响和机制具有重要意义。病人来源的异体移植模型（patient-derived xenograft, PDX）是最具代表性的原发肿瘤体内模型，能够最大程度保留临床肺癌患者肿瘤分子、遗传和异质性特点。本项目利用PDX模型，关注PM2.5对肺腺癌的影响，收集北京(BPM)和石家庄(SPM)两个特大城市的PM2.5，并比较北京和石家庄PM2.5的不同成分和来源，发现汽车尾气排放是BPM的主要来源，而SPM主要是工业排放。我们从分子、细胞、临床样本等多个层次，利用肺腺癌细胞系和PDX模型，研究京津冀地区两个城市(北京和石家庄)PM2.5对肺腺癌发展的影响。观察到PM2.5长期暴露促进肺腺癌在体内的发生和转移，提高肿瘤细胞的侵袭转移能力，这取决于肺腺癌细胞的上皮-间充质转化和肿瘤干细胞特性，肿瘤细胞中与细胞干性相关的蛋白表达上调，肿瘤干细胞相关通路被激活，这些影响在石家庄的样品中更为显著。研究结果对肺癌患者的长期生存及中国特别是首都地区的空气污染治理具有指导意义。