The Emphysematous Microenvironment Promotes Lung Tumorigenesis and Progression

描述（由申请人提供）：在美国，肺癌每年导致超过158，000例死亡，慢性阻塞性肺病（COPD）每年导致超过125，000例死亡，使其成为主要的公共卫生问题。在美国，每一种癌症都比乳腺癌导致更多的女性死亡。COPD患者患肺癌的风险增加，尽管原因尚不清楚。本申请中提出的研究旨在检验肺气肿的发展与肺中促进肺癌发展和生长的微环境相关的假设。这一假设将通过四种方法进行检验。利用匹兹堡大学癌症研究所（UPCI）已经招募的早期肺癌患者的大型队列的信息，将严格的定量分析技术应用于胸部CT扫描，以确定初始扫描时肺气肿的存在和程度是否预测1期肺癌的长期生存。肺癌的位置将与肺内肺气肿的分布和癌症生长的速率相关，以解决肺气肿是否是风险增加的全球标志物，或者肿瘤是否更可能在肺气肿更严重的区域发展和生长更快的问题。将使用最先进的基因组学和蛋白质组学技术分析在癌症手术治疗期间切除的肺组织以及血液样本，以检验以下假设：在肺气肿个体中出现的肺癌周围的肺中存在更多炎症，并且这种肺部炎症可以在血液中循环的某些蛋白质的水平中测量。最后，将使用肺气肿和肺癌的小鼠模型来定义与肺气肿相关的炎症促进肿瘤生长和扩散的机制，测试炎症细胞释放的某些蛋白酶不仅有助于肺破坏而且有助于肿瘤发展和生长的假设。总之，这些研究有可能提供所需的信息，以确定COPD人群中肺癌风险最高的患者，根据COPD状态确定诊断为早期肺癌的复发风险高或低的个体，并提供有关开发新疗法以治疗肺癌和COPD的COPD途径的信息。 公共卫生相关性：我们建议研究与肺癌和慢性阻塞性肺疾病（COPD）相关的两个重要领域。我们将严格分析胸部CT扫描，以确定肺癌发展和进展的高风险个体，并将对人体组织和动物模型进行实验，以确定导致这种高风险的机制。这些结果有可能影响肺癌的筛查和治疗方法，肺癌是美国男性和女性死亡的主要癌症原因。

DESCRIPTION (provided by applicant): Lung cancer is responsible for more than 158,000 deaths and chronic obstructive pulmonary disease (COPD) is responsible for more than 125,000 deaths annually in the US, making them major public health issues. Each is responsible for more deaths in women in the US than breast cancer. Patients with COPD are at increased risk for the development of lung cancer, although the reasons for this are unclear. The research proposed in this application is designed to test the hypothesis that the development of emphysema is associated with a microenvironment in the lung that fosters the development and growth of lung cancer. This hypothesis will be tested by four approaches. Utilizing information from a large cohort of patients with early stage lung cancer already recruited at the University of Pittsburgh Cancer Institute (UPCI), rigorous quantitative analytic techniques will be applied to CT scans of the chest to determine whether the presence and extent of emphysema on the initial scan predicts long-term survival in Stage 1 lung cancer. The location of lung cancers will be correlated with the distribution of emphysema within the lungs and the rate of cancer growth to address the question of whether emphysema is a global marker for increased risk or if tumors are more likely to develop and grow faster in areas of worse emphysema. Lung tissue removed during surgical treatment of the cancer, as well as blood samples, will be analyzed using state-of-the-art genomic and proteomic techniques to test the hypothesis that there is more inflammation in the lung surrounding lung cancers that arise in individuals with emphysema and that this lung inflammation is measurable in the levels of certain proteins circulating in the blood. Lastly, a mouse model of emphysema and lung cancer will be used to define the mechanisms by which inflammation associated with emphysema promotes tumor growth and dissemination, testing the hypothesis that certain proteases released by inflammatory cells not only contribute to lung destruction but also to tumor development and growth. Taken together, these studies have the potential to provide needed information to identify patients within the COPD population who are at highest risk for lung cancer, identify those individuals who are diagnosed with early stage lung cancer who are at high or low risk for recurrence based on their COPD status, and provide information about which COPD pathways to target in developing new therapies to treat both lung cancer and COPD. PUBLIC HEALTH RELEVANCE: We propose to study two important areas related to lung cancer and chronic obstructive pulmonary disease (COPD). We will rigorously analyze chest CT scans to identify individuals at high risk for development and progression of lung cancer and we will perform experiments with human tissue and animal models to ascertain the mechanisms responsible for this high risk. The results have the potential to impact approaches to screening for and treatment of lung cancer, the leading cancer cause of death among men and women in the United States.