Helicobacter pylori infects half the world and is the principal cause of gastric cancer, the second leading cause of cancer death worldwide. However, universal eradication is not feasible and there is a strong need to identify persons at high risk for cancer development and develop new strategies for intervention. We have directly implicated phosphorylation of the epidermal growth factor receptor (pEGFR) and induction of spermine oxidase (SMO) in the aberrant signaling response to H. pylori in gastric epithelial cells. Our published and preliminary data show that oxidation of the polyamine spermine by SMO results in generation of H2 02 that is the cause of DNA damage in infected gastric epithelial cells, and that pEGFR is required for SMO expression and mediates the generation of a subpopulation of cells with SMO-driven DNA damage that are resistant to apoptosis. These events occur in conditionally immortalized gastric epithelial cells and in in vivo models of gastric carcinogenesis (INS-GAS mice and Mongolian gerbils), and human tissues exhibit a strong correlation of SMO and DNA damage. Inhibition of polyamine synthesis or SMO reduces gastric dysplasia and carcinoma in gerbils. Our phosphoproteomics and human tissue microarray studies have implicated EGFR and ErbB2 signaling in addition to SMO in the initiation of gastric carcinogenesis. Additionally, depletion of polyamines in vitro and in vivo reduces oxidative DNA damage and carcinoma despite substantially increasing pEGFR. Our hypothesis is that polyamines determine the effects of EGFR phosphorylation on H. pylori-induced inflammation, DNA damage, and gastric carcinogenesis.
Our Specific Aims are to determine the following in H. pylori-induced gastric carcinogenesis: 1) the role of EGFR transactivation and apoptosis-resistant cells;2) if polyamines are required for the deleterious effects of pEGFR;and 3) the positive and negative regulators of EGFR signaling that are involved. These studies will incorporate unique in vitro and ex vivo models such as gastric organoids, and proven models of gastric dysplasia and carcinoma in mice and gerbils that are employed across this PPG to pursue these aims. We will benefit from continued close collaborations with Projects 1 and 3 that will include exchange of H. pylori mutant strains and output strains from our different animals systems, sharing of samples and expertise related to signaling, and our analysis of SMO-induced oxidative stress and DNA damage. This project will leverage the exceptional quality of Histopathology Core A for Aims 1-3 and Proteomics Core 8 for Aim 3, and will benefit from the uniquely strong environment at Vanderbilt for studies of H. pylori and gastric cancer.

Public Health Relevance

Helicobacter pylori is a type of bacteria that infects the stomach of half of the world's human population, and can lead to the development of gastric cancer, the second leading cause of cancer death worldwide. This project will utilize cell and animal model systems to assess novel molecular pathways altered by H. pylori that lead to cells with damaged DNA that are abnormally resistant to cell death. Our studies seek to define new strategies for prevention of H. pylori-induced gastric cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA116087-06
Application #
8632348
Study Section
Special Emphasis Panel (ZCA1-RPRB-C (O1))
Project Start
2014-01-01
Project End
2018-12-31
Budget Start
2014-03-12
Budget End
2014-12-31
Support Year
6
Fiscal Year
2014
Total Cost
$280,150
Indirect Cost
$81,541
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Coburn, Lori A; Singh, Kshipra; Asim, Mohammad et al. (2018) Loss of solute carrier family 7 member 2 exacerbates inflammation-associated colon tumorigenesis. Oncogene :
Loh, John T; Beckett, Amber C; Scholz, Matthew B et al. (2018) High-Salt Conditions Alter Transcription of Helicobacter pylori Genes Encoding Outer Membrane Proteins. Infect Immun 86:
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:

Showing the most recent 10 out of 203 publications