The major goals of this project over the past 10 years have been to determine the contribution of neutrophil elastase (NE) and alpha-1-antitrypsin ((1AT) to the pathogenesis of COPD. Cigarette smoke exposure is the primary risk factor for both COPD and lung cancer, and literature suggests that the presence of COPD increases the risk of lung cancer. To begin to address the relationship between COPD and lung cancer, we propose the overall hypothesis that neutrophils and NE known effectors in the development of COPD also promote lung cancer progression. To address this we have developed a transgenic model of bronchogenic adenocarcinoma, (CC10-Cre/LSL-K- rasG12D), that possess a chemokine and inflammatory cell profile similar to that found in human lung adenocarcinomas that harbor mutant K-ras. We present additional data that NE, promotes lung tumor growth and angiogenesis in this model of lung cancer. Specifically, we will address three hypotheses: 1) Hypothesis: NE promotes lung tumor growth in a murine model of bronchogenic adenocarcinoma. NE deficient mice (NE-/-) display reduced tumor burden and reduced angiogenesis in our lung cancer model, and within the tumors in vivo, and in vitro studies demonstrate a positive effect of NE on tumor cell proliferation. We propose experiments to determine the mechanisms involved in NE-mediated tumor progression. 2) We hypothesize that CXC chemokine-CXCR-2- mediated PMN recruitment is essential for lung tumor growth and angiogenesis and will utilize BMT experiments to demonstrate this. We will ask whether CXCR-2 enhances tumor growth via its direct effect on angiogenesis or indirectly through PMN recruitment, with the PMN effect being at least in part secondary to angiogenesis. 3) We hypothesize that the recruitment and activation of PMN by cigarette smoke that characterizes COPD also aids lung tumor progression. We will also determine if degree of emphysema, perhaps by decreasing clearance of carcinogens, promotes tumorigenesis. These studies should lead to further insight into the importance and mechanisms of inflammation in lung cancer, which are clearly required if novel therapeutics are to be developed to treat this disease. ? ? ? ?
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