Although the association between chronic epithelial cell inflammation and malignancy is well recognized, the pathophysiological mechanisms mediating the enhanced potential for malignancy in inflammatory states remain unknown. Chronic inflammation of the biliary tract such as in primary sclerosing cholangitis or hepatolithiasis is characterized by alterations in the cytokine milieu and predisposes to the development of neoplasia. With the support of a K08 award (DK02678), we have demonstrated the role of the mitogen activated protein kinase (MAPK) signaling pathways in the proliferation of human cholangiocytes in response to inflammatory mediators. We have also identified aberrant activation of the p38 MAPK signaling pathway in malignant, but not in non-malignant, cholangiocytes. Furthermore, we have shown that p38 MAPK signaling enhances anchorage independent growth, decreases expression of the cell cycle regulator p21WAF1/CIP1, and modulates sensitivity to chemotherapy in malignant cholangiocytes. Thus, our OVERALL HYPOTHESIS is that aberrant p38 MAPK signaling is a critical mediator of malignant transformation in biliary epithelia. Our application has two Specific Aims. FIRST, we will assess the role of p38 MAPK in phenotypic changes of malignant cells, namely invasion and metastases, as well as in the modulation of angiogenesis. SECOND, we will determine the role of p38 MAPK and p21WAF1/CIP1 on cell survival signaling pathways and their relationship to chemosensitivity. We will use a variety of biochemical and molecular approaches for in vitro studies on human normal and malignant cholangiocyte cells in culture and an in vivo xenograft model of cholangiocarcinoma. These studies will help us to elucidate the role of p38 MAPK signaling in the growth and spread of malignant cholangiocytes and provide fundamental insights into the role of cell survival signaling pathways as determinants of chemosensitivity. This information will ultimately contribute to the development of specific therapies for biliary tract malignancies, as well as interventions to treat or prevent neoplasia during chronic inflammation.
