Chronic Inflammation and Lung Tumorigenesis.
Although the causal relationship between inflammation, immunity, and cancer is widely accepted, many of the molecular and cellular mechanisms mediating this relationship remain uncharacterized. Neutrophils account for a significant portion of the inflammatory infiltrate found in a wide variety of cancers and may have a significant impact on the tumor microenvironment via their production of cytokines and chemokines. In addition, reactive oxygen species produced by neutrophils may regulate cell proliferation, angiogenesis, and metastases. However, little is known about how neutrophil infiltration into the lung contributes to the development of lung cancer, making it difficult to identify mechanism(s) or potential targets for prevention and therapy development. Using a mouse model of inflammatory promotion of lung adenocarcinoma that employs the carcinogen 3-methylcholanthrene (MCA) and the tumor promoting lung inflammatory agent butylated hydroxytoluene (BHT), we recently reported that neutrophil infiltration into the lung is a major contributor of lung tumor development. Our goal is to determine the role of neutrophils in mediating these pro-tumorigenic inflammatory processes, and additionally evaluate pharmacologic interventions that could be employed as prevention or therapy in lung cancer. Currently, we are interested in elucidating the role of the macrophage-derived neutrophil chemokine KC/CXCL1, which mediates the recruitment and activation of neutrophils via the CXCR2 receptor, and the role of the neutrophil-derived oxidant generating enzyme myeloperoxidase.
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