Common Pathogenetic Mechanisms of Lung Cancer and COPD

DESCRIPTION (provided by applicant): Together, lung cancer and chronic obstructive pulmonary disease (COPD) are the leading cause of death related to lung disease in the US. Accumulating data indicate that the presence of COPD increases the risk of lung cancer independent of smoking. COPD is highlighted by chronic inflammation initiated by inhaling oxidant species during tobacco combustion. The idea that chronic inflammation is a risk factor for malignancy is not new as several chronic inflammatory diseases are harbingers of cancer. These strong inferences about the links between chronic inflammation and cancer are further buttressed by recent studies linking inflammation to the tumor suppressor gene, p53 and proto-oncogene Ras. Until quite recently, conventional thinking about the genesis of solid tumors has been that the process begins in epithelial cells with somatic or germ line loss of function mutations in key tumor suppressor genes. There is strong experimental evidence to shift this paradigm demonstrating that tumor associated fibroblasts and the extracellular matrix profoundly influence tumor biology. It is therefore apparent that the stroma of the COPD lung is a highly inflammatory, fibrotic milieu; one that we hypothesize is a fertile ground for promoting and nurturing oncogenic mutations resulting from tobacco carcinogens or other exogenous or intrinsic oncogenic stresses. We propose to conduct a comprehensive genome-wide examination of COPD tissue specimens- at the level of the genome, transcriptome, genome-wide ribosome translational profile and proteome - to discover neoplastic gene expression patterns in the COPD lung that are harbingers of carcinogenesis. If successful, these results will identify biomarkers that predict those COPD patients at risk of developing lung cancer, identify therapeutic targets for chemoprevention and thus alter the course of these deadly diseases.