The Emphysematous Microenvironment Promotes Lung Tumorigenesis and Progression

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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.