The Emphysematous Microenvironment Promotes Lung Tumorigenesis and Progression

描述(申请人提供)：在美国，每年有超过15.8万人死于肺癌，超过12.5万人死于慢性阻塞性肺疾病(COPD)，这使它们成为主要的公共卫生问题。在美国，这两种疾病导致的女性死亡人数都高于乳腺癌。COPD患者患肺癌的风险增加，尽管原因尚不清楚。在这项申请中提出的研究旨在检验肺气肿的发展与肺内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)已经招募的一大批早期肺癌患者的信息，严格的定量分析技术将被应用于胸部CT扫描，以确定初始扫描时肺气肿的存在和程度是否预测第一阶段肺癌的长期生存。肺癌的位置将与肺气肿在肺内的分布和癌症生长速度相关联，以解决肺气肿是否是风险增加的全球标志，或者肿瘤是否更有可能在肺气肿严重的地区发展和生长更快的问题。在癌症手术治疗过程中取出的肺组织以及血液样本将使用最先进的基因组和蛋白质组技术进行分析，以检验这样一种假设，即患有肺气肿的人在肺癌周围的肺部有更多的炎症，这种肺部炎症可以通过血液中循环的某些蛋白质水平来衡量。最后，将使用肺气肿和肺癌的小鼠模型来确定与肺气肿相关的炎症促进肿瘤生长和扩散的机制，验证炎症细胞释放的某些蛋白水解酶不仅有助于肺部破坏，而且有助于肿瘤的发展和生长的假设。综上所述，这些研究有可能提供必要的信息，以确定COPD人群中肺癌风险最高的患者，根据他们的COPD状况确定那些被诊断为早期肺癌的高或低复发风险的人，并提供关于在开发治疗肺癌和COPD的新疗法时针对哪些COPD途径的信息。

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.