Clarification of control mechanisms for metastasis/invasion in pancreatic cancer

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We previously reported that the neurotrophic factor, GDNF, has an important role in the invasive capability of pancreatic cancer cells. Furthermore, we confirmed that increased IL-lalpha expression is a feature of liver-metastatic pancreatic cancer cell lines and that IL-lalpha enhances adhesion molecule integrins expression and metastatic potential in pancreatic cancer cell lines via IL-1 receptor type I (IL-1RI). The aims of this study were to identify the role of GDNF and inflammatory cytokines for pancreatic cancer cell proliferative, adhesive, and invasive capabilities.We report the results that we acquired till now as follows.1. GDNF and IL-lalpha significantly enhanced the expression of a6β1 and a5β1-integrins through the activation of transcription factors such as NF-kB and AP-1.2. In all intrapancreatic nerves GDNF was expressed strongly. In pancreatic cancer tissues, the expression of RET was stronger than that seen in normal ductal cells and was significantly related to the survival rate after resection and lymphatic invasion.3. Alteration of ILK kinase activity controlled p38 MAPK phosphorylation with subsequent regulation of pancreatic cancer cell adhesion and invasion. Overexpressed ILK enhances the p38 MAPK phosphorylation strongly through GSK-3 activation which promotes aggressive capabilities of pancreatic cancer cells. In immunohistochemical analysis, statistically significant association between strong expression of ILK and poor prognosis of pancreatic cancer patients were observed.4. FAK activation correlated with the activation of Ras/ERK signaling pathways in pancreatic cancer cells and activation of these signaling pathways can be inhibited by knockdown of FAK expression with siRNA, consistent with the inhibition of adhesive and invasive capabilities of pancreatic cancer cells.