Precursor Of Gastric Cancer Research Articles

Evidence of Epstein-Barr virus association with gastric cancer and non-atrophic gastritis.

Different lines of evidence support an association between Epstein-Barr virus (EBV) and gastric cancer (GC). The main understood risk factor to develop GC is infection by Helicobacter pylori (H. pylori), which triggers a local inflammatory response critical for progression from gastritis to GC. The role of EBV in early inflammatory gastric lesions has been poorly studied. A recent study proposed a cutoff value of 2000 EBV particles to identify patients with increased chances of infection of the gastric epithelium, which may favor the inflammatory process. To better understand the role of EBV in cancer progression, we analyzed 75 samples of GC, 147 control samples of non-tumor gastric tissue derived from GC patients and 75 biopsies from patients with non-atrophic gastritis (NAG). A first-round PCR was used for EBV detection in tumor and non-tumor controls and a more sensitive nested PCR for gastritis samples; both PCRs had lower detection limits above the proposed cutoff value. With this strategy 10.67% of GC, 1.3% of non-tumor controls and 8% of gastritis samples were found positive. An EBER1 in situ hybridization showed EBV infection of epithelial cells in GC and in a third of NAG samples, while in the other NAGs infection was restricted to the mononuclear cell infiltrate. EBV-positive GCs were enriched in lace and cribriform patterns, while these rare patterns were not observed in EBV negative samples. Our results support a role for EBV in GC and early precursor lesions, either as directly oncogenic infecting epithelial cells or indirectly as an inflammatory trigger.

The genetic diversity of Helicobacter pylori virulence genes is not associated with gastric atrophy progression.

Atrophy of the gastric mucosa is a precursor of intestinal-type gastric cancer, and Helicobacter pylori infection causes atrophic gastritis. The aim of this study was to determine whether the genetic diversity of H. pylori virulence genes is associated with the development and progression of gastric atrophy in humans. We isolated and cultured H. pylori strains from patients with gastric ulcer and duodenal ulcer accompanied by atrophic gastritis in background mucosa. H. pylori strains were stored at －80℃ prior to the experiments being carried out. We analyzed iceA, babA, vacA, cagA, and cagE genes by PCR. The cagA gene was analyzed through sequencing of the C-terminal region containing the EPIYA motif, which is related to tyrosine phosphorylation. Severe atrophy was observed in patients with gastric ulcer. The major phenotype of the vacA gene was s1c/m1 (93%). The cagA gene was detected in all strains. The cagE gene was not detected in 2 and 5 strains from the mild cases and severe cases, respectively. The major cagA EPIYA motif, which is amino acids repeat in the C terminus, was the A-B-D type (44 of 58 strains). The virulence genes were not statistically associated with the severity of atrophy in the background gastric mucosa in humans. Not only identification of bacterial virulence factors but also studies of the host response will be necessary to investigate the progression of gastric atrophy and subsequent cancer development in humans.

Letter: gastric atrophy as a precursor of gastric cancer – authors’ reply

The clinico-pathological assessment (and natural history) of autoimmune gastritis (AG) is a matter of debate.1 In their appreciated letter,2 Barbosa and Botelho de Carvalho suggest starting with the histological evidence of corpus-restricted gastritis as a reliable marker of autoimmunity targeting the oxyntic cell population. However, if we do, we should be aware that these ‘putative-AG’ patients include cases whose corpus inflammation/atrophy is part of a multifocal atrophic gastritis due to Helicobacter pylori infection. In our trial,3 we ‘cleansed’ our study population by requiring serology-confirmed gastric autoimmunity. Consistent with this choice, our study sample included 52 patients with antiparietal/anti-intrinsic factor antibodies, with corpus-predominant gastritis, but no histological evidence of corpus-restricted gastric atrophy. Among the patients with positive serology, 116 were followed up for longer than 24 months. At the end of the follow-up, 2 of the 6 cases enrolled as having non-atrophic gastritis featured stage II gastritis, supporting the hypothesis that the natural history of AG includes two subsequent phenotypes: initial non-atrophic and advanced atrophic disease.3 As for the OLGA staging, here again – and also in the autoimmune setting – OLGA staging consistently stratified patients by their different cancer risk.4-7 In fact, the stage of gastritis expresses ‘how advanced’ the disease is, irrespective of its aetiology. In our AG series, all incidental cancers coexisted with high-risk stages, basically confirming both that gastric atrophy is the field in which gastric cancer develops, and the clinical usefulness of staging in gastric cancer secondary prevention strategies.5 As for carcinoids, the related risk coincides with the histological score for corpus atrophy (more than with the OLGA stage): 17 of 19 (89.5%) carcinoids coexisted with score 3 corpus atrophy.3 In conclusion, in the presence of a compatible clinical syndrome, serology does identify autoimmune gastric disease, with a histology that includes both non-atrophic and atrophic phenotypes. Irrespective of the aetiology of gastritis, OLGA staging can convey clinically important information on the gastritis-associated cancer risk. The authors’ declarations of personal and financial interests are unchanged from those in the original article.3

Letter: gastric atrophy as a precursor of gastric cancer

The diagnosis of autoimmune gastritis of theirpatients was based primarily on positive serological testsfor anti-parietal cell and anti-intrinsic factor antibodies.Classically, the criterion for the diagnosis of autoimmunegastritis has been considered to be the selective atrophyof the oxyntic glands of the gastric corpus and fundusassociated with a chronic inflammatory process.We have used this histopathological criterion becauseit is consistent with the presence of serum antibodiesdirected against epitopes of the parietal cells, almost allof them located in these regions of the stomach.

Caspase-1 Has Both Proinflammatory and Regulatory Properties in Helicobacter Infections, Which Are Differentially Mediated by Its Substrates IL-1β and IL-18

The proinflammatory cysteine protease caspase-1 is autocatalytically activated upon cytosolic sensing of a variety of pathogen-associated molecular patterns by Nod-like receptors. Active caspase-1 processes pro-IL-1β and pro-IL-18 to generate the bioactive cytokines and to initiate pathogen-specific immune responses. Little information is available on caspase-1 and inflammasome activation during infection with the gastric bacterial pathogen Helicobacter pylori. In this study, we addressed a possible role for caspase-1 and its cytokine substrates in the spontaneous and vaccine-induced control of Helicobacter infection, as well as the development of gastritis and gastric cancer precursor lesions, using a variety of experimental infection, vaccine-induced protection, and gastric disease models. We show that caspase-1 is activated and IL-1β and IL-18 are processed in vitro and in vivo as a consequence of Helicobacter infection. Caspase-1 activation and IL-1 signaling are absolutely required for the efficient control of Helicobacter infection in vaccinated mice. IL-1R(-/-) mice fail to develop protective immunity but are protected against Helicobacter-associated gastritis and gastric preneoplasia as a result of their inability to generate Helicobacter-specific Th1 and Th17 responses. In contrast, IL-18 is dispensable for vaccine-induced protective immunity but essential for preventing excessive T cell-driven immunopathology. IL-18(-/-) animals develop strongly accelerated pathology that is accompanied by unrestricted Th17 responses. In conclusion, we show in this study that the processing and release of a regulatory caspase-1 substrate, IL-18, counteracts the proinflammatory activities of another caspase-1 substrate, IL-1β, thereby balancing control of the infection with the prevention of excessive gastric immunopathology.

Genetic variation in MUC1, MUC2 and MUC6 genes and evolution of gastric cancer precursor lesions in a long-term follow-up in a high-risk area in Spain

In order to assess whether inherited genetic variability in the mucin genes associates with the evolution of gastric cancer precursor lesions (GCPLs), we genotyped 22 tagSNPs in MUC1, MUC6 and MUC2 genes of 387 patients with GCPLs that had been followed up for 12.8 years. According to the diagnosis at recruitment and at the end of follow-up, the lesions did not change in 43.1% of the patients, regressed in 28.7% and progressed in 28.2%. Three SNPs in the 3'-moiety of MUC2 were significantly associated with a decreased risk of progression of the lesions, whereas another four SNPs, located at the 5'-moiety, were found to be significantly associated either with increased [one single-nucleotide polymorphism (SNP)] or decreased (three SNPs) probability of regression. Stratified analysis indicated that significance was maintained only in those subjects positive for Helicobacter pylori infection and in those not consuming non-steroidal anti-inflammatory drugs, which were found protective against lesion progression. Haplotype analyses indicated the presence of two haplotypes, one in each moiety of the gene, that were significantly associated with decreased risk of progression of the lesions [odds ratio (OR) = 0.49 and 0.46; 95% confidence interval (CI) = 0.28-0.85 and 0.25-0.86, respectively]. The 5'-end haplotype was also associated with increased probability of regression (OR = 1.67; 95% CI = 1.02-2.73), altogether suggesting a protective role against progression of the precancerous lesions. No significant association was found with variants in MUC1 and MUC6 genes. These results indicate, for the first time, that genetic variability in MUC2 is associated with evolution of GCPLs, especially in H.pylori infected patients, suggesting a role of this secreted mucin in gastric carcinogenesis.

Spasmolytic polypeptide-expressing metaplasia (SPEM) in the gastric oxyntic mucosa does not arise from Lgr5-expressing cells

ObjectiveMetaplastic lineages in the oxyntic mucosa of the stomach are critical preneoplastic precursors of gastric cancer. Recent studies have demonstrated that spasmolytic polypeptide-expressing metaplasia (SPEM) in the mouse oxyntic mucosa...

The Role of CD44 in the Pathogenesis, Diagnosis, and Therapy of Gastric Cancer

CD44 is a transmembrane glycoprotein and surface receptor for hyaluronan that is involved in the response of cells to their microenvironment. CD44 splice variants play roles in carcinogenesis, differentiation, and lymph node metastasis and are predictive of the prognosis for various carcinomas, including gastric cancer. Current data suggest that gastric tissue stem cells and gastric cancer stem cells both express the splice variant, CD44v9. Overall, the data regarding the alterations that occur in CD44 and its splice variants in response to acute and chronic infection with Helicobacter pylori are scant and poorly elucidated in terms of possible changes in expression that occur in gastric cancer precursor lesions, such as chronic atrophic gastritis, pyloric metaplasia and intestinal metaplasia. In this study, we discuss the available data and suggest which new data would likely be useful in clinical practice. We also discuss the potential for CD44-targeted therapeutic strategies in gastric cancer. CD44 and its splice variants are positively associated with the initiation and progression of gastric cancer and may also play important roles in diagnosis, therapy and prognosis. CD44 research has been active but fragmented, and it may offer new therapeutic approaches to gastric cancer.

Gastric cancer risk according to the distribution of intestinal metaplasia and neutrophil infiltration

Gastritis and intestinal metaplasia (IM) have long been known to be risk factors for and precursors of gastric cancer. We aimed to elucidate the association between gastric cancer risk and the distribution of precancerous lesions in the stomach by histological analyses. We analyzed patients from whom two biopsy specimens (one from the antrum and one from the corpus) were obtained by upper gastrointestinal endoscopy. Specimens were assessed for Helicobacter pylori, IM, and neutrophil infiltration (NI). Patients were classified into three groups based on the presence of IM. Patients were also classified into four groups based on the presence of NI. The prevalence of gastric cancer was compared between groups. A total of 1395 patients were analyzed. Of these, 54 had gastric cancer (34 intestinal and 20 diffuse type). A multivariate analysis showed that male sex and the distribution of IM were independent risk factors for intestinal-type cancer. Compared with patients without IM (n = 1005), the odds ratio (OR) for patients with IM in the antrum only (n = 240) was 2.34 (95% confidence interval: 1.08-4.96), and that for patients with IM in the corpus (n = 150) was 5.84 (2.92-11.8). However, NI was related to diffuse-type cancer. Compared with patients without NI (n = 899), the OR for patients with NI in the corpus only (n = 122) was 3.66 (1.02-12.2). The histological pattern and distribution of gastric mucosal change assessed by two biopsy specimens were related to gastric cancer.

The C-Terminally Encoded, MHC Class II-Restricted T Cell Antigenicity of the Helicobacter pylori Virulence Factor CagA Promotes Gastric Preneoplasia

Chronic infection with the human bacterial pathogen Helicobacter pylori causes gastritis and predisposes carriers to an increased gastric cancer risk. Consequently, H. pylori-specific vaccination is widely viewed as a promising strategy of gastric cancer prevention. H. pylori strains harboring the Cag pathogenicity island (PAI) are associated with particularly unfavorable disease outcomes in humans and experimental rodent models. We show in this study using a C57BL/6 mouse model of Cag-PAI(+) H. pylori infection that the only known protein substrate of the Cag-PAI-encoded type IV secretion system, the cytotoxin-associated gene A (CagA) protein, harbors MHC class II-restricted T cell epitopes. Several distinct nonoverlapping epitopes in CagA's central and C-terminal regions were predicted in silico and could be confirmed experimentally. CagA(+) infection elicits CD4(+) T cell responses in mice, which are strongly enhanced by prior mucosal or parenteral vaccination with recombinant CagA. The adoptive transfer of CagA-specific T cells to T cell-deficient, H. pylori-infected recipients is sufficient to induce the full range of preneoplastic immunopathology. Similarly, immunization with a cholera toxin-adjuvanted, CagA(+) whole-cell sonicate vaccine sensitizes mice to, rather than protects them from, H. pylori-associated gastric cancer precursor lesions. In contrast, H. pylori-specific tolerization by neonatal administration of H. pylori sonicate in conjunction with a CD40L-neutralizing Ab prevents H. pylori-specific, pathogenic T cell responses and gastric immunopathology. We conclude that active tolerization may be superior to vaccination strategies in gastric cancer prevention.

Polymorphisms in MUC1, MUC2, MUC5B and MUC6 genes are not associated with the risk of chronic atrophic gastritis

Mucins represent major components of the mucous layer in the stomach, protecting the underlying epithelium from acid, mechanical trauma, proteases and pathogenic bacteria. Previous studies have shown an association of neoplastic transformation in the stomach with aberrant mucin levels, suggesting a potential role of genetic variation in mucin genes in the development of gastric cancer (GC). We assessed the association of genetic variation in candidate single nucleotide polymorphisms (SNPs) in mucin genes with the risk of chronic atrophic gastritis (CAG), a well-established precursor of GC in the German population-based ESTHER study. We genotyped MUC1 T31T, MUC2 L58P, MUC2 V116M, MUC5B E34G, MUC5B R51W, MUC5B rs2014486 (intronic) and MUC6 V619M for 533 serologically defined CAG cases and 1054 age- and sex-matched controls. None of the analysed SNPs was associated with CAG. However, large studies are needed to disclose or exclude potential weak associations of these SNPs with CAG risk.

Plasma pepsinogens, antibodies against Helicobacter pylori, and risk of gastric cancer in the Shanghai Women's Health Study Cohort

Background:Circulating pepsinogens can indicate atrophic gastritis, a precursor of gastric cancer. We tested the association between gastric cancer and plasma pepsinogens and antibodies against Helicobacter pylori in a case–control study nested in a prospective cohort.Methods:We selected 141 gastric cancer cases and 282 incidence-density sampled controls. Plasma concentrations of pepsinogens 1 and 2 were measured using ELISA kits, and anti-H. pylori antibodies were measured using a kit specific to Chinese strains. Associations were estimated using conditional logistic regression models adjusted for potential confounders.Results:Gastric cancer subjects were more likely to be anti-H. pylori positive than controls, 97 vs 92%. A plasma pepsinogen 1 (PG1) concentration <50 ng ml–1 (15% of cases) was associated with a significantly increased risk of gastric cancer (OR 4.23; (95% CI: 1.86–9.63), whereas a plasma pepsinogen 2 (PG2) concentration >6.6 ng ml–1 (75% of cases) was also associated with a significantly increased risk of gastric cancer (OR 3.62; (95% CI: 1.85–7.09). We also found that the PG1 : 2 ratio had a nearly linear association with gastric cancer risk.Conclusion:Lower plasma PG1 : 2 ratios are associated with a higher risk of gastric cancer. Furthermore, it appears that circulating pepsinogens 1 and 2 may be independently associated with the risk of gastric cancer.

The significance of p53 and Ki-67 expression rate in adenoma and adenocarcinoma of the stomach.

32 Background: Endoscopic submucosal dissection (ESD) is used for the treatment of gastric adenoma as well as early gastric cancer. Gastric adenoma is a well-known precursor of gastric cancer. The aim of this study is to investigate the expression degree of p53 and Ki-67 in gastric adenoma can predict progression to gastric cancer. Methods: We analyzed p53 and Ki-67 expression degree in the tumor tissue of 16 gastric adenoma patients treated by ESD and 11 early gastric cancer patients treated by subtotal gastrectomy at Kangnam Sacred Heart Hospital of Hallym University between November 2008 and May 2009. According to the fraction of stained nuclei in tumor tissue, expression degree was classified as &lt; 10% = negative, 10%∼33% = 1+, 34%∼66% = 2+, &gt; 66% = 3+. Results: Mean age was 65.1 ± 11.5 years and mean tumor size was 33.7 ± 20.2mm. Among 16 gastric adenoma patients, low-grade dysplasia were 11 and high grade dysplasia were 5. p53 positivity was not different between gastric adenoma and gastric cancer, but Ki-67 positivity was significantly different between adenoma and cancer (p &lt; 0.05). In addition, Ki-67 positivity was increasing tendency as the pathology progress from low grade dysplasia to cancer. Conclusions: Ki-67 positivity grade seems to be correlated with malignancy. High Ki-67 positivity in gastric adenoma can predict progression to gastric cancer. Even if endoscopic biopsy showed low grade dysplasia, additional ESD should be preferentially considered in lesions with high Ki-67 positivity. No significant financial relationships to disclose.

Incidence and risk factors for the development of chronic atrophic gastritis: Five year follow‐up of a population‐based cohort study

Chronic atrophic gastritis (CAG) is a well-established precursor of intestinal gastric cancer. However, data on incidence of CAG are rare, especially from population-based studies. The aim of this analysis was to estimate the incidence of CAG in a large population-based study among older adults from Germany and to identify major risk factors associated with its development. In the baseline and 5-year follow-up examinations of the ESTHER study, serological measurements of pepsinogen (PG) I and II and Helicobacter pylori antibodies were performed in 5,229 women and men, aged 50-74 years at baseline. Information on additional potential risk factors was obtained by questionnaire. CAG was defined by PGI < 70 ng/mL and PGI/PGII < 3. In total, there were 58 (1.1%) incident CAG cases. CAG incidence increased with increasing age from 0.5% in age group 50-54 years to 2.1% in age group 70-74 years. Seropositivity with H. pylori was strongly associated with CAG incidence, with adjusted odds ratios of 5.0 [95% confidence interval (CI): 1.6-15.8] and 11.3 (95% CI: 4.2-30.0) for participants with cytotoxin associated gene A (cagA) negative and cagA positive H. pylori infection at both baseline and follow-up compared to those without H. pylori infection, respectively. Gender, education, smoking, alcohol consumption and family history of gastric cancer were not significantly associated with CAG incidence. Incidence of CAG is rather low in the German population. Older age and infection with H. pylori are key risk factors for the development of CAG.

Interobserver Variation in the Diagnosis of Gastric Epithelial Dysplasia and Carcinoma between Two Pathologists in Japan and Korea

Although the biological potential of gastric epithelial dysplasia (GED) as a precursor of gastric cancer has never been in doubt, the classification of these lesions has been controversial and fraught with marked variations in approach to diagnosis across the world. The complexity of cyto-architectural features has been considered to be of paramount importance for the diagnosis of carcinoma in Japan, while breach of the basement membrane and invasion into the lamina propria has been considered the sine qua non of malignancy and hence a pre-requisite for the diagnosis of cancer in the West. In Korea, although the incidence of gastric cancer is similar to Japan, the diagnostic approach to GED or cancer seems to lie midway between Western and Japanese criteria. In this review, we will discuss the difference in the diagnosis of GED and cancer between two pathologists working in the comprehensive cancer center located in Japan and Korea, one of the most prevalent areas in the world for gastric cancer.

Screening of Helicobacter pylori Infection After Gastrectomy for Cancer or Peptic Ulcer

Gastric cancer commonly follows a long-standing inflammation, mainly due to Helicobacter pylori (HP) infection. After resection, the stump develops precancerous alterations. Prospective study of patients undergoing endoscopy from April 1, 2000, through March 31, 2006. University departments of Surgery and Experimental Medicine and Pathology. One hundred eighty-seven patients receiving upper gastrointestinal tract endoscopy many years after surgery for duodenal ulcer or gastric cancer. Ten to 12 postoperative endoscopic biopsy samples were taken from the remnant stomach. The risk of gastric cancer precursor lesions associated with HP infection. The gastric cancer precursor lesions were more common in the entire HP-positive population (odds ratio [OR], 2.37; 95% confidence interval [CI], 1.25-4.49; P = .007). However, HP-positive patients undergoing resection for cancer had a higher risk of the precursor lesions compared with HP-negative patients in the same diagnostic group (OR, 4.20; 95% CI, 1.10-15.96) and all patients undergoing resection for duodenal ulcer (OR, 1.59; 95% CI, 0.44-5.73). The results of this investigation support the role of HP in gastric carcinogenesis and suggest that the HP eradication therapy might prevent the development of metachronous gastric cancer after gastric resection.

Inhibition of ADP Ribosylation Prevents and Cures Helicobacter-Induced Gastric Preneoplasia

Gastric adenocarcinoma develops as a consequence of chronic inflammation of the stomach lining that is caused by persistent infection with the bacterium Helicobacter pylori. Gastric carcinogenesis progresses through a sequence of preneoplastic lesions that manifest histologically as atrophic gastritis, intestinal metaplasia, and dysplasia. We show here in several preclinical models of Helicobacter-induced atrophic gastritis, epithelial hyperplasia, and metaplasia that the inhibition of ADP ribosylation by the small-molecule inhibitor PJ34 not only prevents the formation of gastric cancer precursor lesions, but also efficiently reverses preexisting lesions. PJ34 exerts its chemopreventive and therapeutic effects by impairing Helicobacter-specific T-cell priming and T(H)1 polarization in the gut-draining mesenteric lymph nodes. The subsequent infiltration of pathogenic T cells into the gastric mucosa and the ensuing gastric T cell-driven immunopathology are prevented efficiently by PJ34. Our data indicate that PJ34 directly suppresses T-cell effector functions by blocking the IFN-gamma production of mesenteric lymph node T cells ex vivo. Upon exposure to PJ34, purified T cells failed to synthesize ADP-ribose polymers and to activate the transcription of genes encoding IFN-gamma, interleukin 2, and the interleukin 2 receptor alpha chain in response to stimuli such as CD3/CD28 cross-linking or phorbol 12-myristate 13-acetate/ionomycin. The immunosuppressive and chemoprotective effects of PJ34 therefore result from impaired T-cell activation and T(H)1 polarization, and lead to the protection from preneoplastic gastric immunopathology. In conclusion, ADP-ribosylating enzymes constitute novel targets for the treatment of Helicobacter-associated gastric lesions predisposing infected individuals to gastric cancer and may also hold promise for the treatment of other T cell-driven chronic inflammatory conditions and autoimmune pathologies.

Tolerance Rather Than Immunity Protects From Helicobacter pylori–Induced Gastric Preneoplasia

Chronic infection with the bacterial pathogen Helicobacter pylori causes gastric disorders, ranging from chronic gastritis to gastric adenocarcinoma. Only a subset of infected persons will develop overt disease; most remains asymptomatic despite lifelong colonization. This study aims to elucidate the differential susceptibility to H pylori that is found both across and within populations. We have established a C57BL/6 mouse model of H pylori infection with a strain that is capable of delivering the virulence factor cytotoxin-associated gene A (CagA) into host cells through the activity of a Cag-pathogenicity island-encoded type IV secretion system. Mice infected at 5-6 weeks of age with CagA(+)H pylori rapidly develop gastritis, gastric atrophy, epithelial hyperplasia, and metaplasia in a type IV secretion system-dependent manner. In contrast, mice infected during the neonatal period with the same strain are protected from preneoplastic lesions. Their protection results from the development of H pylori-specific peripheral immunologic tolerance, which requires transforming growth factor-β signaling and is mediated by long-lived, inducible regulatory T cells, and which controls the local CD4(+) T-cell responses that trigger premalignant transformation. Tolerance to H pylori develops in the neonatal period because of a biased ratio of T-regulatory to T-effector cells and is favored by prolonged low-dose exposure to antigen. Using a novel CagA(+)H pylori infection model, we report here that the development of tolerance to H pylori protects from gastric cancer precursor lesions. The age at initial infection may thus account for the differential susceptibility of infected persons to H pylori-associated disease manifestations.

Prostaglandin E2 Prevents Helicobacter-Induced Gastric Preneoplasia and Facilitates Persistent Infection in a Mouse Model

Persistent infection with the human pathogen Helicobacter pylori increases the risk of gastric cancer. In this study, we investigated the role of cyclooxygenase-2 (COX-2) and its main product, prostaglandin E(2) (PGE(2)), in the development of Helicobacter-induced gastritis and gastric cancer precursor lesions. We utilized mouse models of Helicobacter-induced gastric preneoplasia and vaccine-induced protection to study the effects of COX-2 inhibition and PGE(2) treatment on the induction of Helicobacter-specific immune responses and gastric premalignant immunopathology. COX-2 and PGE(2) are up-regulated upon Helicobacter infection in cultured epithelial cells and in the gastric mucosa of infected mice. Inhibition of COX-2 activity with celecoxib significantly accelerated early preneoplasia; conversely, systemic administration of synthetic PGE(2) prevented development of premalignant pathology and completely reversed preexisting lesions by suppressing interferon-gamma production in the infected stomachs. The protective effect of PGE(2) was accompanied by increased Helicobacter colonization in all models. All in vivo effects were attributed to immunosuppressive effects of PGE(2) on CD4(+) T-helper 1 cells, which fail to migrate, proliferate, and secrete cytokines when exposed to PGE(2) in vitro and in vivo. T-cell inhibition was found to be due to silencing of interleukin-2 gene transcription, and could be overcome by supplementation with recombinant interleukin-2 in vitro and in vivo. COX-2-dependent production of PGE(2) has an important immunomodulatory role during Helicobacter infection, preventing excessive local immune responses and the associated immunopathology by inhibiting the effector functions of pathogenic T-helper 1 cells.

Inverse association between a pro-inflammatory genetic profile and Helicobacter pylori seropositivity among patients with chronic atrophic gastritis: Enhanced elimination of the infection during disease progression?

Background Helicobacter pylori infection is a key risk factor for chronic atrophic gastritis (CAG), an established precursor of gastric cancer. There is increasing evidence of frequent clearance of the infection during progression of CAG. We aimed to assess the association between host inflammatory polymorphisms and H. pylori seropositivity among CAG patients from Germany. Methods In the baseline examination of ESTHER, a population-based study conducted in Saarland, serum pepsinogens I and II and H. pylori serostatus were measured by ELISA, and selected genetic polymorphisms (IL1A C-889T, IL1B C-511T, IL1RN A9589T, IL8 T-251A, IL10 T-819C, IL10 A-1082G, LTA C+80A and TNFA G-308A) were assessed by Pyrosequencing™ for 534 serologically defined CAG cases. Results H. pylori seropositivity strongly decreased with disease severity, which is defined by quintiles of serum pepsinogen I, from higher than 90% in the least severe cases to hardly over 50% in the most severe cases. The pro-inflammatory genotypes IL10 -819CC and IL1RN 9589TT were significantly associated with decreased H. pylori seroprevalences with odds ratios of 0.45 (95% confidence interval (CI): 0.23–0.88) and 0.41 (95% CI: 0.18–0.92), respectively, after controlling for age, sex and disease severity. H. pylori seropositivity decreased with the number of pro-inflammatory genotypes ( p < 0.01). Conclusions Our results disclose a clear inverse association between a pro-inflammatory genetic profile and H. pylori seropositivity among cases with CAG, supporting suggestions of enhanced elimination of H. pylori during the development of the disease.