COBRE Pilot Project for Nancy Webb: Center of Research in Obesity and Cardiovascular Disease

Obesity is associated with an increased risk of several types of cancer. The biological mechanisms underlying increased cancer risk in obesity are not well understood, but inflammatory processes are thought to be involved. We propose that elevated levels of serum amyloid A (SAA) provide a link between obesity, inflammation, and an increased risk for cancer. SAA exerts a variety of activities important in innate immunity, including cytokine induction, leukocyte chemotaxis, and upregulation of genes involved in extracellular matrix remodeling. All of these activities are characteristic of tissue microenvironments that are permissive for tumor growth and metastasis. Furthermore, results from our laboratory and others’ indicate that SAA activates the inflammasome, leading to secretion of interleukin (IL)-1B linked to tumor growth and metastasis. The possibility that systemic SAA promotes cancer would have important implications for obese individuals, where circulating SAA is known to be chronically elevated. Aim 1: To investigate the role of systemic SAA in promoting metastasis in a mouse model of lung cancer. Control LLC cells and LLC cells with stable suppression or overexpression of SAA will be injected into wild-type C57BL/6 mice and C57BL/6 mice lacking SAA. Hepatic SAA expression will be increased in a subset of mice using adeno-associated viral (AAV) vectors. Lung tumor burden and markers of inflammasome activation in tumors will be assessed. Aim 2: To test the hypothesis that SAA promotes metastasis through increased production of IL-1B SAA overexpression will be injected into C57BL/6 mice and C57BL/6 mice lacking the IL-1B inflammasome activation in tumors will be assessed. Findings from the mouse model will be translated to humans by screening human lung tumor-derived cell lines and tissue microarrays of human non-small cell lung cancers for SAA and IL-1B studies of SAA in mouse models of obesity-induced cancer, and ultimately, cancer risk in obese human patients.