Helicobacter pylori and gastric cancer

Helicobacter pylori is now well known as an important pathogen related to the development of gastric cancer. However, some clinicians still doubt the causal association of H. pylori with the development of gastric cancer. To summarize the recent clinical data on the link between H. pylori and gastric cancer, we reviewed related articles published over the past 3 years, after the award of the Nobel Prize for Physiology or Medicine to Drs. J.R. Warren and B.J. Marshall for the first culture and isolation of H. pylori and the investigation of their relevance to peptic ulcer disease. This updated summary of the relationship between H. pylori and gastric cancer highlights the strong link between the organism and the development of gastric cancer, and suggests eradication of this bacterial infection as a possible prophylactic measure against the development of this lethal malignancy. At present, clinicians and researchers in the field emphasize the strong need for H. pylori eradication from the human stomach.     

幽门螺杆菌感染及其相关因素与胃癌关系的研究进展

 胃癌是人类最常见的恶性肿瘤之一,目前研究认为幽门螺杆菌（HP）是胃癌发生发展进程的重要推动因素,现就目前国内外学者对HP在胃癌发生中致病的毒力因子及作用机制、宿主基因的易感性和环境因素三个方面进行综述。     

Helicobacter pylori infection and gastric cancer

The pathogenesis of gastric cancer (GC) includes a sequence of events that begins with Helicobacter pylori-induced chronic superficial gastritis, progressing towards atrophic gastritis, intestinal metaplasia, dysplasia and eventually GC. The association between H. pylori and GC is supported by experimental data showing a capacity of H. pylori to induce GC in animals, and the results of interventional studies showing that H. pylori eradication can lower the risk of GC and prevent development of pre-cancerous lesions in humans and in experimental animals. The "driving force" of gastric carcinogenesis is a chronic gastric inflammation, whose intensity and localisation depending on bacterial, host and environmental factors, determines the risk of GC. The mechanisms by which chronic inflammation lead to epithelial and pre-cancerous lesions include induction of oxidative stress, perturbation of the epithelial cells proliferation/apoptosis ratio, and cytokine secretion. Several molecular alterations associated with gastric carcinogenesis have also been described.     

幽门螺杆菌与残胃癌

残胃癌发病与幽门螺杆菌感染密切相关,幽门螺杆菌能促进残胃黏膜上皮细胞增殖,促进胃液中亚硝基化合物的产生及人体某些基因异常表达,最终促使残胃癌发生.根除幽门螺杆菌感染有望减少残胃癌的发生.     

Epidemiology of Helicobacter pylori and gastric cancer

Findings in epidemiological studies of the relationship between Helicobacter pylori and gastric cancer have been inconsistent: many studies have yielded a positive relationship, whereas several studies have shown no relationship. The inconsistency arises because of the occurrence of seroreversion during the period between the time that H. pylori exerts a carcinogenic effect and the time of blood sampling. When this seroreversion is taken into account, there is an epidemiologically positive association between H. pylori status and the risk for gastric cancer. In addition to the epidemiological evidence, experimental studies using Mongolian gerbils have shown that H. pylori infection elevates the risk for gastric cancer. It is concluded that H. pylori is a causal factor for gastric cancer. In the creation of preventive strategies against gastric cancer by the eradication of H. pylori, determination of the time at which H. pylori plays a role as a carcinogen is important. Three hypotheses have been proposed in regard to this timing: that H. pylori infection in childhood or the teenage years acts as a factor that produces precancerous lesions with irreversible damage in the gastric mucosa, that in adulthood it acts as an initiator, and also in adulthood, that it acts as a promoter. As these hypotheses are not mutually exclusive, the extent to which each hypothesis plays a part in explaining gastric carcinogenesis should be evaluated. Only a small proportion of subjects infected with H. pylori have gastric cancer during their lifetime. Interleukin-1 polymorphism, a host factor, and CagA, a virulence factor of H. pylori, are suspected to be risk factors for gastric cancer in subjects with H. pylori infection. Dietary factors, especially vitamin C, and patterns of precancerous lesions also seem to influence the relationship between H. pylori and gastric cancer. H. pylori seems to reduce the risk for esophageal and for some gastric cardia adenocarcinomas. This finding, as well as determination of the time at which H. pylori exerts this preventive effect, should be considered in the creation of preventive strategies against gastric cancer that target the eradication of H. pylori. Received: June 1, 2001 / Accepted: October 16, 2001     

Effect of age on the relationship between gastric cancer and Helicobacter pylori. Tokyo Research Group of Prevention for Gastric Cancer.

Helicobacter pylori is thought to be involved in the pathogenesis of gastric cancer, but the time point at which it produces its effects (critical time) is unknown. We measured the serum level of H. pylori antibody in 787 gastric cancer patients and 1007 controls aged 20 to 69. Odds ratios for different gastric cancer types and stages were determined for each 10-year age class. The overall odds ratio for gastric cancer decreased with age, being 7.0 for those aged 20 - 29, 14.5 for those aged 30 - 39, 9.1 for those aged 40 - 49, 3.5 for those aged 50 - 59, and 1.5 for those aged 60 - 69 (trend in odds ratios: P < 0.01). However, there was no such age-dependent trend for early diffuse-type cancer; the odds ratios were 12.6, 4.0, 7.2, 6.5, and 18.5 respectively (P = 0.29). Early cancer tended to show higher seroprevalence than advanced cancer, especially in older subjects. No significant difference in seroprevalence was observed between diffuse and intestinal cancers within each age-class. Seroreversion must have occurred in the time interval between the critical time and the diagnosis of the cancer, especially in older patients. The age-dependent relationship between H. pylori and gastric cancer may be due to seroreversion, which itself may be independent of age. This age-independence indicates that prolonged exposure to H. pylori does not increase the magnitude of its influence on gastric carcinogenesis. Possible mechanisms through which H. pylori exerts pathogenic effects are continuous inflammation in adulthood and / or irreversible damage to gastric mucosa in childhood or the teenage years.     

Helicobacter pylori and gastric cancer prevention is possible

Epidemiological data gathered during the past few years have shown an association between Helicobacter pylori infection and gastric carcinoma. This association is considered to be causal because of its biological plausibility and the existence of an animal model, even though the positive consequences of eradication on cancer prevention have not yet been definitely proven. The limited proportion of H. pylori infected subjects who develop a gastric cancer can be explained by host factors (certain alleles of IL-1beta) and bacterial factors (cag positive strains), and to a lesser extent by environmental factors (diet). Arguments in favor of the prevention of gastric carcinoma by eradicating H. pylori are now stronger than before, given the availability of simple and accurate diagnostic tests (serology) and treatment follow-up (urea breath test), as well as a 7-day treatment which is usually sufficient for eradication.     

Helicobacter pylori,gastric microbiota and gastric cancer relationship: Unrolling the tangle

Helicobacter pylori infection (Hp-I) represents a typical microbial agent intervening in the complex mechanisms of gastric homeostasis by disturbing the balance between the host gastric microbiota and mucosa-related factors, leading to inflammatory changes, dysbiosis and eventually gastric cancer. The normal gastric microbiota shows diversity, with Proteobacteria [Helicobacter pylori (H. pylori) belongs to this family], Firmicutes, Actinobacteria, Bacteroides and Fusobacteria being the most abundant phyla. Most studies indicate that H. pylori has inhibitory effects on the colonization of other bacteria, harboring a lower diversity of them in the stomach. When comparing the healthy with the diseased stomach, there is a change in the composition of the gastric microbiome with increasing abundance of H. pylori (where present) in the gastritis stage, while as the gastric carcinogenesis cascade progresses to gastric cancer, the oral and intestinal-type pathogenic microbial strains predominate. Hp-I creates a premalignant environment of atrophy and intestinal metaplasia and the subsequent alteration in gastric microbiota seems to play a crucial role in gastric tumorigenesis itself. Successful H. pylori eradication is suggested to restore gastric microbiota, at least in primary stages. It is more than clear that Hp-I, gastric microbiota and gastric cancer constitute a challenging tangle and the strong interaction between them makes it difficult to unroll. Future studies are considered of crucial importance to test the complex interaction on the modulation of the gastric microbiota by H. pylori as well as on the relationships between the gastric microbiota and gastric carcinogenesis.     

Helicobacter pylori infection and gastric cancer: facing the enigmas

At an individual level Helicobacter pylori was associated with the occurrence of gastric cancer but in some African and Asian countries its prevalence runs with low gastric cancer rates, the so-called African and Asian enigmas. We assessed whether the association between gastric cancer and H. pylori prevalence at an area level is modified by the level of exposure to fruits and vegetables, alcohol or tobacco. Regression models were fitted to data from 58 countries using as dependent variable log transformed gastric cancer rates and as independent covariables the H. pylori prevalence, fruits and vegetables consumption, cigarette smoking, alcohol intake and interaction terms. The levels of alcohol consumption or cigarette smoking modified the association between gastric cancer and H. pylori infection. Models including H. pylori prevalence, alcohol consumption, cigarette smoking and the interaction terms H. pylori x alcohol or H. pylori x tobacco were used to compute gastric cancer incidence multiplying regression coefficients by a H. pylori prevalence of 85% (the approximate median in African countries) and the median figures observed in each continent for alcohol and tobacco availability. The expected gastric cancer incidence per 100,000 would be 5.7 assuming the alcohol and tobacco availability in African countries, 7.0 in Asia and Oceania, 16.0 in America and 26.0 in Europe. The interaction between H. pylori and cigarette or alcohol consumption may contribute to further explain the international variation in gastric cancer and the so-called African and Asian enigmas.     

Severe atrophic gastritis with Helicobacter pylori infection and gastric cancer

Background. We conducted a case-control study to evaluate whether patients with severe gastric atrophy (indicated by serum pepsinogen concentration) have a high risk of gastric cancer. Methods. At the time of diagnosis of gastric cancer, sera from 301 patients (cases) and 602 sex- and age-matched cancer-free individuals (controls) were tested for the presence of anti-Helicobacter pylori IgG antibody (HM-CAP enzyme-linked immunoassay [ELISA] kit; Kyowa Medix, Tokyo, Japan) and serum pepsinogen (PG) levels (PG I and II Riabead Kits; Dainabot, Tokyo, Japan). We defined positivity for pepsinogen a pepsinogen I concentration of less than 70 ng/mL and a PG I/II ratio of less than 3.0. We categorized the subjects according to serum pepsinogen levels and anti-Helicobacter pylori IgG antibody, creating four categories. Results. Of the 301 cancer cases, 177 had positive serum pepsinogen levels, and 172 were positive for anti-Helicobacter pylori IgG antibody. The category in which subjects had positive serum pepsinogen levels and were negative for anti-Helicobacter pylori IgG antibody had the highest proportion (76.9%) of individuals with gastric cancer and the highest odds ratio (4.20) of the four categories. The odds ratios were 2.55 (95% confidence interval; 1.92–3.88) for positive serum pepsinogen levels and 0.93 (95% confidence interval; 0.63–1.27) for positive anti-Helicobacter pylori IgG antibody. Conclusion. These results suggest that patients with positive serum pepsinogen levels who are negative for IgG antibody to Helicobacter pylori, constitute a high-risk group for gastric cancer. Helicobacter pylori infection is associated with the development of gastric cancer by providing a suitable environment i.e., severe gastric atrophy, for carcinogenesis of the gastric mucosa. Received for publication on Mar. 20, 1998; accepted on Aug. 20, 1998     

Performance of gastric cancer screening by endoscopy testing through the National Cancer Screening Program of Korea

Recent reports have proposed endoscopy as an alternative strategy to radiography for gastric cancer (GC) screening. The current study presents the first reported population-based data from a large GC screening program that provided endoscopic examinations. A retrospective population-based study was conducted using the National Cancer Screening Program (NCSP) database. We evaluated GC detection rates, sensitivity, specificity, and the positive predictive value of an endoscopic screening program for the average-risk Korean population, aged 40 years and older, who underwent the NCSP from 2002 to 2005. The detection rates of GC by endoscopy in the first and subsequent rounds were 2.71 and 2.14 per 1000 examinations, respectively. Localized cancer accounted for 45.7% of screen-detected GC cases. The sensitivity of endoscopy was 69% (95% confidence interval [CI]: 66.3-71.8). The endoscopic screening was less sensitive for the detection of localized GC (65.7%, 95% CI = 61.8-69.5) than for regional or distant GC (73.6%, 95% CI = 67.4-79.8). In the multiple logistic models for localized GC and all combined GC, the odds ratio (OR) of sensitivity for the undifferentiated type was statistically significantly higher than that for the differentiated type, whereas the OR of sensitivity for the mixed type was lower than that for the differentiated type. The sensitivity of the endoscopic test in a population-based screening was slightly higher for the detection of regional or distant GC than for localized GC. Further evaluation of the impact of endoscopic screening should take into account the balance of cost and mortality reduction.     

Helicobacter pylori infection in relation to gastric cancer progression

Gastric cancer is a major cause of cancer death worldwide, especially in developing countries. The incidence of gastric cancer varies from country to country, probably as a result of genetic, epigenetic, and environmental factors. H. pylori infection is considered as a major risk factor in the development of gastric cancer. However, the scenario varies in Asian countries, exhibiting a higher rate of H. pylori infection and low incidence of gastric cancer, which could be attributed to strain-specific virulence factors and host genetic makeup. In this review, we discuss the various virulence factors expressed by this bacterium and their interaction with the host factors, to influence pathogenesis.