Inflammatory mechanisms contributing to pancreatic cancer development

Objective: Pancreatic cancer is the most deadly of all gastrointestinal (GI) malignancies, yet relatively little is known regarding mechanisms of tumor development including the role of inflammation. Summary Background Data: Chronic pancreatitis (CP) increases the risk of developing cancer by 10- to 20-fold- mediators of the chronic inflammatory process and the surrounding fibrotic stroma likely support a transformation to malignancy, yet the exact mechanisms remain undefined. The purpose of our present study was to determine potential inflammatory components in epithelial and stromal cells that may contribute to both CP and pancreatic cancers. Methods: Specimens of normal pancreas, CP, and pancreatic cancer were examined using laser-capture microdissection (LCM), gene array, and immunohistochemistry. Results: Gene array analysis from LCM-dissected tissues demonstrated: (i) increased expression of interleukin-8 (IL-8), an activator of the inflammatory factor nuclear factor-kappaB (NF-kappaB), and (ii) decreased expression of IkappaB (an inhibitor of NF-kappaB) in CP ductal cells compared with normal ducts. Compared with CP, cancers demonstrated: (i) increased expression of tumor related genes including S100A4, cyclin E1, and epidermal growth factor (EGF) receptor, and (ii) expression of matrix metalloproteinase 2, a pro-invasive factor for tumor cells, which was not present in the CP stroma. Increased staining of both the p50 NF-kappaB Subunit and IKKalpha kinase (a protein that allows activation of NF-kappaB) was noted in CP and cancers. Conclusions: Our results demonstrate that similar inflammatory components and downstream effectors are present in CP and pancreatic cancers. Importantly, these findings suggest that a common pathway for pancreatic cancer development may be through a chronic inflammatory process including stroma formation. These findings may lead to novel strategies for pancreatic cancer prophylaxis based on inhibition of inflammatory mediators.