The etiology of H. pylori-induced gastric cancer is multifactorial, but one important component is the dysregulated immune response that leads to chronic inflammation and resulting cellular damage. Our lab has discovered a novel pathway for the generation of oxidative stress-induced DNA damage in H. pylori- iniected gastric epithelial cells that results from oxidation of the polyamine spermine by the enzyme spermine oxidase (SMO), producing hydrogen peroxide (H2O2). Increased substrate for SMO is generated by synthesis of polyamines from L-ornithine by the enzyme ornithine decarboxylase (ODC). We have also previously implicated nitric oxide (NO), reporting that the enzyme inducible NO synthase (INOS) that produces high levels of NO, a known mutagen, is upregulated by H. pylori in vitro and in vivo. Work supported by this P01 has demonstrated dramatically different rates of gastric cancer in Colombia, such that individuals from the high risk region of the Andean mountains have a 25-fold greater risk of developing cancer than those from the low risk coastal region, despite identical prevalence rates of H. pylori infection. Our preliminary studies using genotype-matched H. pylori clinical isolates indicate that when compared to strains from the low risk region, strains from the high risk region induce significantly more SMO and oxidative DNA damage in gastric epithelial cells in vitro that correlates with similar findings in the gastritis tissues from the source patients for these strains. We also found that high risk strains induce more INOS in vitro and in vivo. Importantly, we show that Colombian clinical isolates can infect mice and gerbils, and that a high risk strain induces dyplasia in gerbils. Evolutionary analysis of 6 strains by multi-locus sequence typing revealed that the 3 strains from the high risk region clustered together and with reference strains of European origin and the 3 strains from the low risk region clustered together and with strains of African origin. Our hypothesis is that oxidative stress from SMO, and nitrosative stress from iNOS are determinants of neoplastic risk in H. pylori infection, and these pathways are differentially modulated by H. pylori strains from regions of high vs. low gastric cancer risk.
Our Specific Aims are: 1.) To demonstrate that H. pylori strains from the high vs. low gastric cancer risk region exhibit increased ability to induce responses that lower the threshold for carcinogenesis;2.) To demonstrate that polyamine synthesis by ODC, oxidation of spermine by SMO, and generation of NO by INOS are mediators of gastric cancer risk in vivo;and 3.) To define microbial determinants of oxidative and nitrosative stress, and gastric cancer risk by studying H. pylori strains from longitudinal Colombian cohorts in adults and children. The studies proposed are innovative and tightly ntegrated with this P01 as a whole, as they seek to define specific mechanisms of gastric carcinogenesis induced by H. pylori strains from regions of divergent cancer risk in the Colombian natural laboratory.

Public Health Relevance

(See Instructions): This project examines damage to the stomach lining caused by oxygen radicals and nitric oxide in order to determine if these agents have a causal role in the gastric cancer induced by H. pylori.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA028842-28
Application #
8540093
Study Section
Special Emphasis Panel (ZCA1-GRB-P)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
28
Fiscal Year
2013
Total Cost
$213,321
Indirect Cost
$38,846
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Garay, Jone; Piazuelo, M Blanca; Majumdar, Sumana et al. (2016) The homing receptor CD44 is involved in the progression of precancerous gastric lesions in patients infected with Helicobacter pylori and in development of mucous metaplasia in mice. Cancer Lett 371:90-8
Murray-Stewart, T; Sierra, J C; Piazuelo, M B et al. (2016) Epigenetic silencing of miR-124 prevents spermine oxidase regulation: implications for Helicobacter pylori-induced gastric cancer. Oncogene 35:5480-5488
Yang, Ines; Woltemate, Sabrina; Piazuelo, M Blanca et al. (2016) Different gastric microbiota compositions in two human populations with high and low gastric cancer risk in Colombia. Sci Rep 6:18594
Sobota, Rafal S; Kodaman, Nuri; Mera, Robertino et al. (2016) Epigenetic and genetic variation in GATA5 is associated with gastric disease risk. Hum Genet 135:895-906
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
Camargo, M Constanza; Kim, Kyoung-Mee; Matsuo, Keitaro et al. (2016) Anti-Helicobacter pylori Antibody Profiles in Epstein-Barr virus (EBV)-Positive and EBV-Negative Gastric Cancer. Helicobacter 21:153-7
Dubeykovskaya, Zina; Si, Yiling; Chen, Xiaowei et al. (2016) Neural innervation stimulates splenic TFF2 to arrest myeloid cell expansion and cancer. Nat Commun 7:10517
Singh, Kshipra; Al-Greene, Nicole T; Verriere, Thomas G et al. (2016) The L-Arginine Transporter Solute Carrier Family 7 Member 2 Mediates the Immunopathogenesis of Attaching and Effacing Bacteria. PLoS Pathog 12:e1005984
Dixon, Beverly R E A; Radin, Jana N; Piazuelo, M Blanca et al. (2016) IL-17a and IL-22 Induce Expression of Antimicrobials in Gastrointestinal Epithelial Cells and May Contribute to Epithelial Cell Defense against Helicobacter pylori. PLoS One 11:e0148514
Hardbower, Dana M; Asim, Mohammad; Murray-Stewart, Tracy et al. (2016) Arginase 2 deletion leads to enhanced M1 macrophage activation and upregulated polyamine metabolism in response to Helicobacter pylori infection. Amino Acids :

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