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.
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.
|Noto, Jennifer M; Chopra, Abha; Loh, John T et al. (2018) Pan-genomic analyses identify key Helicobacter pylori pathogenic loci modified by carcinogenic host microenvironments. Gut 67:1793-1804|
|Butt, Julia; Blot, William J; Teras, Lauren R et al. (2018) Antibody Responses to Streptococcus Gallolyticus Subspecies Gallolyticus Proteins in a Large Prospective Colorectal Cancer Cohort Consortium. Cancer Epidemiol Biomarkers Prev 27:1186-1194|
|Shen, Xi; Liu, Liping; Peek, Richard M et al. (2018) Supplementation of p40, a Lactobacillus rhamnosus GG-derived protein, in early life promotes epidermal growth factor receptor-dependent intestinal development and long-term health outcomes. Mucosal Immunol 11:1316-1328|
|Mera, Robertino M; Bravo, Luis E; Camargo, M Constanza et al. (2018) Dynamics of Helicobacter pylori infection as a determinant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial. Gut 67:1239-1246|
|Singh, Kshipra; Coburn, Lori A; Asim, Mohammad et al. (2018) Ornithine Decarboxylase in Macrophages Exacerbates Colitis and Promotes Colitis-Associated Colon Carcinogenesis by Impairing M1 Immune Responses. Cancer Res 78:4303-4315|
|Corley, Douglas A; Peek Jr, Richard M (2018) When Should Guidelines Change? A Clarion Call for Evidence Regarding the Benefits and Risks of Screening for Colorectal Cancer at Earlier Ages. Gastroenterology 155:947-949|
|Gobert, Alain P; Al-Greene, Nicole T; Singh, Kshipra et al. (2018) Distinct Immunomodulatory Effects of Spermine Oxidase in Colitis Induced by Epithelial Injury or Infection. Front Immunol 9:1242|
|Raghunathan, Krishnan; Foegeding, Nora J; Campbell, Anne M et al. (2018) Determinants of Raft Partitioning of the Helicobacter pylori Pore-Forming Toxin VacA. Infect Immun 86:|
|Scoville, Elizabeth A; Allaman, Margaret M; Brown, Caroline T et al. (2018) Alterations in Lipid, Amino Acid, and Energy Metabolism Distinguish Crohn's Disease from Ulcerative Colitis and Control Subjects by Serum Metabolomic Profiling. Metabolomics 14:|
|Sierra, Johanna C; Asim, Mohammad; Verriere, Thomas G et al. (2018) Epidermal growth factor receptor inhibition downregulates Helicobacter pylori-induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis. Gut 67:1247-1260|
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