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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA093405-10
Application #
7787031
Study Section
Special Emphasis Panel (ZRG1-DIG-C (02))
Program Officer
Daschner, Phillip J
Project Start
2001-05-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
10
Fiscal Year
2010
Total Cost
$283,150
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Hayakawa, Yoku; Fox, James G; Wang, Timothy C (2017) Isthmus Stem Cells Are the Origins of Metaplasia in the Gastric Corpus. Cell Mol Gastroenterol Hepatol 4:89-94
Hayakawa, Yoku; Fox, James G; Wang, Timothy C (2017) The Origins of Gastric Cancer From Gastric Stem Cells: LessonsĀ From Mouse Models. Cell Mol Gastroenterol Hepatol 3:331-338
Feng, Yan; Mannion, Anthony; Madden, Carolyn M et al. (2017) Cytotoxic Escherichia coli strains encoding colibactin and cytotoxic necrotizing factor (CNF) colonize laboratory macaques. Gut Pathog 9:71
Hayakawa, Yoku; Sakitani, Kosuke; Konishi, Mitsuru et al. (2017) Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling. Cancer Cell 31:21-34
Sakitani, Kosuke; Hayakawa, Yoku; Deng, Huan et al. (2017) CXCR4-expressing Mist1+ progenitors in the gastric antrum contribute to gastric cancer development. Oncotarget 8:111012-111025
Hayakawa, Yoku; Chang, Wenju; Jin, Guangchun et al. (2016) Gastrin and upper GI cancers. Curr Opin Pharmacol 31:31-37
Esmail, Michael Y; Bacon, Rebecca; Swennes, Alton G et al. (2016) Helicobacter Species Identified in Captive Sooty Mangabeys (Cercocebus atys) with Metastatic Gastric Adenocarcinoma. Helicobacter 21:175-85
Burns, Monika; Muthupalani, Sureshkumar; Ge, Zhongming et al. (2015) Helicobacter pylori Infection Induces Anemia, Depletes Serum Iron Storage, and Alters Local Iron-Related and Adult Brain Gene Expression in Male INS-GAS Mice. PLoS One 10:e0142630
Hayakawa, Yoku; Ariyama, Hiroshi; Stancikova, Jitka et al. (2015) Mist1 Expressing Gastric Stem Cells Maintain the Normal and Neoplastic Gastric Epithelium and Are Supported by a Perivascular Stem Cell Niche. Cancer Cell 28:800-814
Wymore Brand, Meghan; Wannemuehler, Michael J; Phillips, Gregory J et al. (2015) The Altered Schaedler Flora: Continued Applications of a Defined Murine Microbial Community. ILAR J 56:169-78

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