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Iron deficiency accelerates Helicobacter pylori-induced carcinogenesis in rodents and humans.

ABSTRACT: Gastric adenocarcinoma is strongly associated with Helicobacter pylori infection; however, most infected persons never develop this malignancy. H. pylori strains harboring the cag pathogenicity island (cag+), which encodes CagA and a type IV secretion system (T4SS), induce more severe disease outcomes. H. pylori infection is also associated with iron deficiency, which similarly augments gastric cancer risk. To define the influence of iron deficiency on microbial virulence in gastric carcinogenesis, Mongolian gerbils were maintained on iron-depleted diets and infected with an oncogenic H. pylori cag+ strain. Iron depletion accelerated the development of H. pylori-induced premalignant and malignant lesions in a cagA-dependent manner. H. pylori strains harvested from iron-depleted gerbils or grown under iron-limiting conditions exhibited enhanced virulence and induction of inflammatory factors. Further, in a human population at high risk for gastric cancer, H. pylori strains isolated from patients with the lowest ferritin levels induced more robust proinflammatory responses compared with strains isolated from patients with the highest ferritin levels, irrespective of histologic status. These data demonstrate that iron deficiency enhances H. pylori virulence and represents a measurable biomarker to identify populations of infected persons at high risk for gastric cancer.

SUBMITTER: Noto JM

PROVIDER: S-EPMC3533289 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Iron deficiency accelerates Helicobacter pylori-induced carcinogenesis in rodents and humans.

Noto Jennifer M JM Gaddy Jennifer A JA Lee Josephine Y JY Piazuelo M Blanca MB Friedman David B DB Colvin Daniel C DC Romero-Gallo Judith J Suarez Giovanni G Loh John J Slaughter James C JC Tan Shumin S Morgan Douglas R DR Wilson Keith T KT Bravo Luis E LE Correa Pelayo P Cover Timothy L TL Amieva Manuel R MR Peek Richard M RM

The Journal of clinical investigation 20121221 1

Gastric adenocarcinoma is strongly associated with Helicobacter pylori infection; however, most infected persons never develop this malignancy. H. pylori strains harboring the cag pathogenicity island (cag+), which encodes CagA and a type IV secretion system (T4SS), induce more severe disease outcomes. H. pylori infection is also associated with iron deficiency, which similarly augments gastric cancer risk. To define the influence of iron deficiency on microbial virulence in gastric carcinogenes ...[more]

PMID: 23257361

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Project description:BACKGROUND & AIMS: Gastric cancer results from a combination of Helicobacter pylori (H pylori) infection, exposure to dietary carcinogens, and predisposing genetic make-up. Because the role of these factors in gastric carcinogenesis cannot be determined readily in human beings, the present study examined the role of an oral carcinogen and H pylori infection in rhesus monkeys. METHODS: Gastroscopies were performed in 23 monkeys assigned to 4 groups: controls; nitrosating carcinogen ethyl-nitro-nitrosoguanidine administration alone; and inoculation of a virulent H pylori strain alone (H), or in combination with ethyl-nitro-nitrosoguanidine (EH). Follow-up gastroscopies and biopsies were performed at 3-month intervals for 5 years for pathologic and molecular studies. RESULTS: Postinoculation, H and EH groups showed persistent infection and antral gastritis. Starting at 2 and 5 years, respectively, gastric intestinal metaplasia and intraepithelial neoplasia developed in 3 EH monkeys but in no other groups. Transcriptional analysis of biopsies at 5 years revealed group-specific expression profiles, with striking changes in EH monkeys, plus a neoplasia-specific expression profile characterized by changes in multiple cancer-associated genes. Importantly, this neoplastic profile was evident in nonneoplastic mucosa, suggesting that the identified genes may represent markers preceding cancer. CONCLUSIONS: Gastric intraglandular neoplasia is induced in primates when H pylori infection is associated with consumption of a carcinogen similar to the nitrosaminesfound in pickled vegetables, suggesting that H pylori and the carcinogen synergistically induce gastric neoplasia in primates. Monkey arrays used for analysis of the affect of Helicobacter pylori and diet on development of gastric cancer. Each RNA was hybridized against a common reference. Biopsy numbers represent the following in terms of descriptions used in publication of the paper... Each set of numbers/descriptions is organized in the following order: Biopsy#; Monkey#; Group Code on Fig 5 Biopsy #4674; AB24; E; E1 Biopsy #4684; 16G; E; E2 Biopsy #4716; 89G; H; H1 Biopsy #4724; 54H; H; H2 Biopsy #4720; 20G; H; H3 Biopsy #4710; 92F; C; C1 Biopsy #4714; 26G; C; C2 Biopsy #4712; 92G; C; C3 Biopsy #4726; 08G; H; H4 Biopsy #4722; 57G; H; H5 Biopsy #4718; 85G; H; H6 Biopsy #4694; 48H; HE NON; HE1 Biopsy #4686; 59H; HE NON; HE2 Biopsy #4690; 81G; HE NEO; HE3 Biopsy #4696; 36G; HE NEO; HE4 Biopsy #4692; 63G; HE NEO; HE5 Biopsy #4680; 76G; E; E3 Biopsy #4682; 52G; E; E4 Biopsy #4678; 15G; E; E5 Biopsy #4676; 93G; E; E6 Biopsy #4688; 47H; HE NON; HE6 A pathogenicity experiment design type is where an infective agent such as a bacterium, virus, protozoan, fungus etc. infects a host organism(s) and the infective agent is assayed. Infection: Rhesus monkeys were infected with H. pylori (+/-) Compound Based Treatment: Rhesus monkeys were treated with ENNG (N-ethyl-N-nitrosoguanidine) (+/-)

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Iron deficiency accelerates Helicobacter pylori-induced carcinogenesis in rodents and humans.

Publications

Iron deficiency accelerates Helicobacter pylori-induced carcinogenesis in rodents and humans.

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