Helicobacter pylori infection has been strongly linked to gastric cancer, and recent studies suggest that a major factor in cancer progression is the inflammatory response to infection. A key factor in inflammatory responses that are linked to carcinogenesis is the transcription factor NF-kB. While NF-kB expression in epithelial cells may function primarily to inhibit apoptosis, activation of NF-kB dinners in macrophages leads to the production of numerous cytokines and chemokines, such as interleukin-1beta and interleuekin-8, that can promote cancer. Work from our group has shown the H. pylori infection can activate NF-kB pathways and cytokine production in macrophages. Furthermore, transgenic overexpression of IL-1beta in the mouse stomach can lead to the spontaneous development of gastric cancer in uninfected mice. Finally, studies from our laboratory suggest that chronic infection of C57BL/6 mice with Helicobacter, a known carcinogen, leads to chronic inflammation and repopulation of the stomach with bone marrow derives stem cells (BMDCs) that then progress to metaplasia, dysplasia to intraepithelial cancer [Science 2004;306:1568-1571]. Given that these tumors are not highly vascularized nor metastatic, we have recently developed an additional transgenic mouse line bearing a physiologically regulated human interleukin-8 (IL-8) transgene. We propose to test the hypotheses that (1) NF-kB activation in macrophages, leading to the production of IL-1beta and IL-8, is critical to the induction of gastric inflammation and (2) that NF-kB activation is gastric epithelial cells is important for gastric stem cell survival and in preventing BMDC engraftment and progression to cancer. We propose to explore the role of inflammation and NF-kB in our murine models of gastric cancer through two aims: (1) Can IL-1beta and IL-8 synergize to induce NF-kB activation in macrophages and BMDCs and accelerate gastric cancer? NF-kB activity will be tracked using cis-NF-kB-EGFP transgenic mice, the source of IL-8 defined, the possible synergy in cancer invasion explored. (2). What is the role of NF-kB in myeloid versus epithelial cells in the Helicobacter mouse model of gatsric cancer? We will use Foxa3-Cre and Mx1- Cre mouse lines crossed to floxed IKKbeta F/F mice to generate condition deletion of IKKbeta in gastric epithelial or myeloid cells, and examine the response to chronic Helicobacter infection. We will test the hypothesis that inhibition of NF-kB in epithelial cell will promote apoptosis and BMDC engraftment.
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