H. pylori is the strongest known risk factor for gastric adenocarcinoma, the second leading cause of cancer-related death worldwide, yet only a fraction of infected persons ever develop this malignancy. One H. pylori determinant that augments cancer risk is the cag type IV secretion system (T4SS), which translocates the microbial oncoprotein GagA into epithelial cells. Our preliminary data generated with Project 2 demonstrate that intracellular delivery of GagA activates B-catenin and that a consequence of Beta catenin activation within H. pylori-infected epithelial cells is hyperproliferation. Our studies have also demonstrated that iron depletion augments the ability of H. pylori to activate Beta-catenin. We have now shown with Gastric Histopathology Core A that iron depletion accelerates the development of H. pylori induced cancer in gerbils in a cagA-dependent manner. Two-dimensional (20) DIGE/mass spectrometry performed by Proteomics Core B identified 33 differentially abundant proteins among H. pylori strains isolated from iron-depleted versus iron-replete gerbils, several of which mediate microbial adherence and function of the cag T4SS. These results directly informed provocative new studies performed with Project 3 demonstrating that H. pylori strains harvested from iron-depleted gerbils or grown under iron-depleted conditions in vitro exhibit an enhanced capacity to assemble the cag T4SS, translocate GagA, and induce expression of proinflammatory cytokines. We have also developed new models of H. pylori infection that more closely recapitulate events occurring within the gastric niche. Gastric organoids are three dimensional, single-layered epithelial organ-like structures, and provide a unique opportunity to study host H. pylori interactions in a pre-clinical model. We have now successfully grown, maintained, characterized, and infected gastric organoids with H. pylori. Our hypothesis is that iron depletion augments H. pylori cag? dependent oncogenesis. We will test this via the following Aims: 1. Define mechanisms that regulate oncogenesis in response to iron deprivation and H. pylori. 2. Define H. pylori-induced carcinogenic responses using a novel ex vivo organoid system. 3. Define differences in epithelial molecular responses to carcinogenic H. pylori versus a cagA- mutant strain using a gerbil model of gastric cancer within the context of iron depletion.

Public Health Relevance

These studies will define bacterial and host factors that influence gastric cancer. Such findings may help to identify H. pylori infected persons at high risk for gastric cancer, who thereby warrant therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZCA1-RPRB-C (O1))
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Vanderbilt University Medical Center
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Hardbower, Dana M; Singh, Kshipra; Asim, Mohammad et al. (2016) EGFR regulates macrophage activation and function in bacterial infection. J Clin Invest 126:3296-312
Riquelme, Ismael; Tapia, Oscar; Leal, Pamela et al. (2016) miR-101-2, miR-125b-2 and miR-451a act as potential tumor suppressors in gastric cancer through regulation of the PI3K/AKT/mTOR pathway. Cell Oncol (Dordr) 39:23-33
Gogoi, Mayuri; Datey, Akshay; Wilson, Keith T et al. (2016) Dual role of arginine metabolism in establishing pathogenesis. Curr Opin Microbiol 29:43-8
Gobert, Alain P; Wilson, Keith T (2016) The Immune Battle against Helicobacter pylori Infection: NO Offense. Trends Microbiol 24:366-76
Beceiro, S; Radin, J N; Chatuvedi, R et al. (2016) TRPM2 ion channels regulate macrophage polarization and gastric inflammation during Helicobacter pylori infection. Mucosal Immunol :
Zhao, Gang; Liu, Liping; Peek Jr, Richard M et al. (2016) Activation of Epidermal Growth Factor Receptor in Macrophages Mediates Feedback Inhibition of M2 Polarization and Gastrointestinal Tumor Cell Growth. J Biol Chem 291:20462-72
Peek Jr, Richard M (2016) New Biology to New Treatment of Helicobacter pylori-Induced Gastric Cancer. Dig Dis 34:510-6
Chen, Jinjing; Wang, Zhen; Hu, Xiangming et al. (2016) BET Inhibition Attenuates Helicobacter pylori-Induced Inflammatory Response by Suppressing Inflammatory Gene Transcription and Enhancer Activation. J Immunol 196:4132-42
Amieva, Manuel; Peek Jr, Richard M (2016) Pathobiology of Helicobacter pylori-Induced Gastric Cancer. Gastroenterology 150:64-78
Varga, Matthew G; Piazuelo, M Blanca; Romero-Gallo, Judith et al. (2016) TLR9 activation suppresses inflammation in response to Helicobacter pylori infection. Am J Physiol Gastrointest Liver Physiol 311:G852-G858

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