Clarification of control mechanisms for adhesion molecules and metastasis/invasion mechanisms by cytokines to contribute to cure pancreatic cancer

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We have shown that up-regulated IL-1alpha expression is a feature only of liver-metastatic pancreatic cancer cell lines. Furthermore, we confirmed that increased IL-1alpha expression is a feature of liver-metastatic pancreatic cancer cell lines, in contrast to low-metastatic pancreatic cancer cell lines, and that IL-1alpha enhances adhesion molecule 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 integrins and intracellular signaling transduction for pancreatic cancer cell proliferative, adhesive, and invasive capabilities.We report the results that we acquired till now as follows.1.Both HUVEC proliferation and tube formation were strongly enhanced by co-culture with metastatic pancreatic cancer cells and were enhanced to a similar extent by culture in the presence of IL-1alpha. In contrast, blockade of IL-1alpha by IL-1ra inhibited HUVEC proliferation and angiogenesis.2.The role o … More f NF-kappaB in signaling transduction pathways was investigated.(1)Proliferation of pancreatic cancer cell lines was decreased by a proteasome inhibitor in a dose-dependent manner, and the proliferative capabilities of Ikappa-B dominant negative vector-transfected pancreatic cancer cells were also inhibited. The invaded cell number and the NF-kappaB activity were increased by GDNF stimulation. However, in the presence of a proteasome inhibitor or Ikappa-B dominant negative vector, which blocks the nuclear localization of NF-kappaB, both were significantly suppressed. Furthermore, reduced activity of both remained unchanged by GDNF stimulation.(2)Treatment with signaling transduction inhibitors, such as ERK-1/2 and p38 MAPK inhibitors, prevented the activation of transcription factor AP-1. It can be suggested that AP-1 is a downstream target of MAPK pathways and that ERK-1/2 and p38 MAPK may mediate the IL-1alpha-induced enhancements of proliferative and invasive capabilities of pancreatic cancer cells through AP-1 activation. Less