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.     

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.     

Development of gastric cancer associated with Helicobacter pylori infection

Helicobacter pylori infection is associated with histological gastritis, gastric atrophy, gastric cancer and mucosa-associated lymphoid tissue lymphoma in the stomach. However, gastric cancer only develops in a minority of infected individuals. Such clinical diversity is caused by variations in the interactions between H. pylori pathogenicity, host susceptibility, and environmental factors. Based on evidence from three prospective epidemiological studies, the International Agency for Research on Cancer and the World Health Organization (IARC/WHO) concluded in 1994 that H. pylori has a causal linkage to gastric carcinogenesis and is a definite carcinogen in humans. Two large-scale, prospective, epidemiological studies have recently been reported in Japan and have confirmed that H. pylori infection constitutes a high risk factor for the development of gastric cancer, at least in males. In order to obtain evidence that eradication of H. pylori leads to a reduction in the occurrence of gastric cancer, reversibility of precancerous lesions, gastric atrophy or intestinal metaplasia should be proven after eradication treatment. A biopsy specimen from the lesser curvature of the corpus is the most sensitive for evaluating the regression of gastric atrophy on histology, and the evaluation needs be conducted at least 13 months after treatment. In a Mongolian gerbil model with or without low-dose chemical carcinogens, it has been demonstrated that H. pylori can lead to the development of gastric cancer. Experimental studies have elucidated that virulence factors of H. pylori interact with gastric epithelial cell signaling related to carcinogenesis. The cag pathogenicity island (cagPAI) is a major virulence gene cluster; it encodes the type IV secretion machinery system forming a cylinder-like structure. The CagA protein is translocated into target cells via this secretion system and induces a hummingbird phenotype, a growth factor-like effect. The other gene products are probably translocated into target cells and accelerate cellular proliferation and apoptosis. The molecular mechanism of the interaction between H. pylori and gastric epithelial cells may provide a new strategy for effective prevention of the development of gastric cancer induced by H. pylori infection.     

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     

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.     

Helicobacter pylori infection predicts favorable outcome in patients with gastric cancer

Background

Recent studies have suggested a controversial role of Helicobacter pylori infection in gastric cancer prognosis. The aim of the present study was to investigate the potential impact of H. pylori status on the prognosis of patients with gastric cancer in a Chinese prospective cohort.

Methods

Between 2007 and 2009, 261 patients with curatively resected gastric cancer were enrolled in the study. H. pylori status was defined by means of immunohistochemical staining in tumour and non-neoplastic tissues. Treatment prognosis was measured in terms of cancer-specific survival and disease-free survival (dfs). Univariate and multivariate Cox regression models were used to assess the association between H. pylori status and patient prognosis.

Results

Positivity for H. pylori infection was observed in 188 of the 261 patients (72.0%). In patients positive for H. pylori, mean cancer-specific survival was 55.2 months [95% confidence interval (ci): 53.4 to 56.9 months] and mean dfs was 53.9 months (95% ci: 51.8 to 56.0 months); the same survivals were, respectively, 45.1 months (95% ci: 42.2 to 47.9 months) and 43.7 months (95% ci: 40.4 to 47.0 months) in patients negative for H. pylori. In univariate analysis, positive H. pylori status was associated with better cancer-specific survival [hazard ratio (hr): 0.486; 95% ci: 0.271 to 0.870; p = 0.015] and dfs (hr: 0.540; 95% ci: 0.307 to 0.950; p = 0.033). In multivariate analysis, H. pylori was an independent prognostic factor for cancer-specific survival (hr: 0.485; 95% ci: 0.265 to 0.889; p = 0.019).

Conclusions

Our study demonstrates that positive H. pylori status is a beneficial prognostic indicator in patients with gastric cancer and might suggest possible therapeutic approaches for gastric cancer. Further research is required to better understand inflammation mechanisms and cancer progression.     

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     

CagA+ Helicobacter pylori infection and gastric cancer risk in the EPIC-EURGAST study

Helicobacter pylori (H. pylori), atrophic gastritis, dietary and life-style factors have been associated with gastric cancer (GC). These factors have been evaluated in a large case-control study nested in the European Prospective Investigation into Cancer and Nutrition carried out in 9 countries, including the Mediterranean area. Participants, enrolled in 1992-1998, provided life-style and dietary information and a blood sample (360,000; mean follow-up: 6.1 years). For 233 GC cases diagnosed after enrolment and their 910 controls individually-matched by center, gender, age and blood donation date H. pylori antibodies (antilysate and antiCagA) and plasma Pepsinogen A (PGA) were measured by ELISA methods. Severe chronic atrophic gastritis (SCAG) was defined as PGA circulating levels <22 microg/l. Overall, in a conditional logistic regression analysis adjusted for education, smoke, weight and consumption of total vegetables, fruit, red and preserved meat, H. pylori seropositivity was associated with GC risk. Subjects showing only antibodies anti-H. pylori lysate, however, were not at increased risk, while those with antiCagA antibodies had a 3.4-fold increased risk. Overall, the odds ratio associated with SCAG was 3.3 (95% CI 2.2-5.2). According to site, the risk of noncardia GC associated with CagA seropositivity showed a further increase (OR 6.5; 95% CI 3.3-12.6); on the other hand, a ten-fold increased risk of cardia GC was associated with SCAG (OR 11.0; 95% CI 3.0-40.9). These results support the causal relationship between H. pylori CagA+ strains infection, and GC in these European populations even after taking into account dietary habits. This association was limited to distal GC, while serologically defined SCAG was strongly associated with cardia GC, thus suggesting a divergent risk pattern for these 2 sites.     

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 infection and gastric carcinogenesis in animal models

The effects of Helicobacter pylori infection on gastric disorders have been proven by many epidemiological and experimental studies. To explore the relationships between H. pylori infection and gastric carcinogenesis, many factors, including host responses, environmental status, and the virulence factors of the bacteria should be taken into account. Mongolian gerbils ( Meriones unguiculatus ) can be easily infected with H. pylori , and provide an excellent in-vivo experimental model to clarify the role of H. pylori in active gastritis, peptic ulcers, intestinal metaplasia, and gastric carcinoma. Studies have revealed that H. pylori infection markedly enhances all histological types of gastric cancers in gerbils treated with a chemical carcinogen. Eradication reduced the enhancing effect of H. pylori on gastric carcinogenesis, whereas a high-salt diet synergistically enhanced the effect of H. pylori . Various factors involving inflammation, cell proliferation, and cell differentiation could be examined with this experimental model to help elucidate this mechanisms of gastric carcinogenesis. Received: October 23, 2002 / Accepted: December 9, 2002 Acknowledgments We thank Dr. Toshiko Kumagai, Central Clinical Laboratories, Shinshu University Hospital; Dr. Atsushi Sugiyama, First Department of Surgery, Shinshu University; Professor Tsutomu Katsuyama, Department of Laboratory Medicine, Shinshu University School of Medicine; and Dr. Nobuyuki Shimizu and Professor Michio Kaminishi, Department of Gastrointestinal Surgery, Postgraduate School of Medicine, The University of Tokyo. Offprint requests to: M. Tatematsu     

Helicobacter pylori infection in intestinal- and diffuse-type gastric adenocarcinomas

Gastric cancer can be divided into two histologic types: intestinal and diffuse. To determine whether Helicobacter pylori, a bacterium linked with gastritis, was associated with either cancer type, we reviewed histologic sections from stomachs of patients who had undergone gastrectomy for gastric cancer. Of 37 of the sections with evidence of intestinal-type cancer, 33 (89.2%) contained H pylori in noncancerous tissue compared with 7 (31.8%) of 22 of the sections with evidence of diffuse-type cancer (odds ratio = 17.7; P less than .001). This association remained strong when controlled for age, sex, site, and number of sections reviewed. The prevalence of H pylori in intestinal-type gastric cancer far exceeded the prevalence of H pylori in diffuse disease and that described in the normal US population. This finding suggests that H pylori may be a cofactor in development of intestinal-type gastric cancer.     

Prevalence of Helicobacter pylori infection in gastric remnant after distal gastrectomy for primary gastric cancer

Background. The development of a second primary cancer in the gastric remnant after gastrectomy for early gastric carcinoma is a problem, and eradication of Helicobacter pylori after the operation has been recommended. However, to date, practical indications for H. pylori eradication after gastric cancer surgery have not yet been reported. Methods. We examined H. pylori infection in the gastric remnant after distal gastrectomy for primary gastric cancer. One hundred and nine patients who had had a gastrectomy were studied. Endoscopic findings and results from the urease test, bacteriologic assessment, serological test, and histopathological examination were analyzed. Results. Seventy-one patients (65.1%) were judged to be positive for H. pylori infection. The prevalence of H. pylori infection was found to be significantly decreased in older patients, patients in whom the operation had been performed a long time before examination, patients with symptoms, and patients with severe reflux gastritis. On the other hand, histologically, chronic and acute gastritis correlated significantly with H. pylori infection. H. pylori prevalence was highest in mildly atrophic mucosa and decreased with more extensive atrophic changes of the mucosa. Conclusions. The persistence of H. pylori -related active gastritis in the gastric remnant after gastric cancer surgery was suggested in younger patients with mild atrophic gastritis and without reflux gastritis. These patients may be the best candidates for H. pylori eradication therapy. Received: April 13, 2001 / Accepted: June 18, 2001     

Role of Helicobacter pylori infection among offspring or siblings of gastric cancer patients

A positive family history is an increased risk factor for gastric cancer within family members, and one of the possible causes of this is the intrafamilial clustering of Helicobacter pylori infection. Our study examined the prevalence of H. pylori infection, serum antibodies to CagA and VacA and atrophic gastritis and/or intestinal metaplasia in the offspring or siblings of gastric cancer patients. A total of 726 subjects included 300 relatives of 300 separate gastric cancer patients and 426 controls. All subjects underwent upper gastrointestinal endoscopic examination with a rapid urease test. Blood samples were obtained to test for the presence of serum antibodies to the CagA and VacA proteins of H. pylori. The prevalence of H. pylori infection was higher in relatives of cancer patients (75.3%) than in controls (60.1%), and the adjusted odds ratio was 2.1 (95% CI 1.5-2.9). When either siblings or 2 or more family members were gastric cancer patients, the prevalence of H. pylori infection was much higher compared to the prevalence in controls. There was no specific relationship between CagA and VacA, and H. pylori infection. Atrophic gastritis and/or intestinal metaplasia were more frequently found in H. pylori-infected relatives of cancer patients (26.1%) than in H. pylori-infected controls (12.9%). These results strongly support a role for H. pylori infection in familial aggregation of gastric cancer. The prophylactic eradication of H. pylori infection in the offspring or siblings of gastric cancer patients may be clinically beneficial.     

胃癌组织α-连接蛋白与幽门螺杆菌感染的相关性研究

目的 探讨胃癌发生过程中α-连接蛋白(alpha-catenin,α-Cat)表达与幽门螺杆菌(helicobacter pylori,Hp)感染的关系,及其在胃癌发生发展中的可能机制.方法 选择胃黏膜活检及手术切除的胃癌病理标本96例,癌旁组织96例,对照标本15例.应用免疫组化SP法检测各组组织中α-Cat的表达.用快速尿素酶试验或组织学Warthin-Starry嗜银染色法检测胃黏膜Hp感染情况.结果 α-Cat在胃癌组、癌旁组织组、对照组的阳性表达率分别为34.4%、56.2%、100.0%,胃癌组显著低于癌旁组织组和对照组(P＜0.05); 96例胃癌组织中Hp 阳性组α-Cat表达明显低于Hp阴性组(46.3% vs 59.2%,P＜0.05);α-Cat阳性率在高、中分化和低、未分化型胃癌组织中阳性率呈现递减趋势(69.1% vs 10.7%,P＜0.01),但α-Cat表达和淋巴结转移、癌肿浸润深度无密切相关.结论 在胃黏膜癌变过程中,α-Cat的表达逐渐上调.胃癌组织中α-Cat的表达与Hp感染相关,提示Hp感染可通过对α-Cat表达的影响,在胃癌的发生发展过程中发挥一定作用.     

Role of Helicobacter pylori infection and chronic inflammation in gastric cancer in the cardia

BACKGROUND: Helicobacter pylori-induced gastritis is an important factor for gastric carcinogenesis. However, it is still controversial whether it is also applicable for cardiac cancer development. Recently, we reported that H. pylori is an important factor for the induction of cardiac inflammation. We examined the status of H. pylori-induced gastritis in patients with cardiac cancer. METHODS: Seventy-five Japanese patients (58 men; mean age, 64.2 years) with cardiac cancer were studied. Cardiac cancer was defined as that mainly located within 2 cm from the squamo-columnar junction (SCJ). Histological gastritis including the cardiac region was evaluated using the biopsy or surgically resected sections. Cardiac inflammation was evaluated at 1 cm distal from SCJ in lesser curvature. Sera were collected and several markers were evaluated. The status of H. pylori infection was evaluated by histology and serum antibodies. Expressions of cytokeratins were examined by immunohistochemical analysis. RESULTS: Out of 75 patients with cardiac cancer, H. pylori was positive in 71 (95%) patients. The cardiac inflammation was examined in 30 patients (26 with H. pylori and four without H. pylori infection) and we found cardiac inflammation was present in all cases with H. pylori infection. Histologically, H. pylori-related gastritis was also found in the gastric corpus and antrum. Serological data were consistent with the presence of chronic atrophic gastritis. Intestinal metaplasia was found in 18 cases in the cardiac mucosa, and their cytokeratin 7/20 pattern was judged as a gastric pattern in all cases. CONCLUSION: H. pylori infection is closely associated with cardiac cancer.     

Helicobacter pylori infection and gastric diseases--pathogenesis and effects of eradication

H. pylori infection is associated with major gastroduodenal diseases, i.e. peptic ulcer, cancer and MALT lymphoma in the stomach. The pathogenesis of H. pylori in these diseases has been elucidated. Non-atrophic diffuse antral gastritis is correlated with duodenal ulcer and multifocal atrophic gastritis is correlated with both gastric ulcer and cancer. It is well known that Japanese tend to have multifocal atrophic gastritis. H. pylori eradication therapy dramatically reduces the recurrence rates of gastroduodenal ulcers in humans and bacterial eradication for peptic ulcer patients has been recommended in many countries. Mongolian gerbils have provided an excellent model of gastric carcinogenesis and H. pylori enhanced (promoted) chemical carcinogen-induced carcinogenesis in the stomach using this model. H. pylori eradication reduced the incidence of gastric cancer in the Mongolian gerbil model. It was a recently discovered that a transforming clone carrying the translocation t (11;18) (q21;q21) forms a MALT lymphoma, the growth of which is independent of H. pylori and will not respond to bacterial eradication. In the early stage, the tumor can be successfully treated by eradication, but at a later stage additional genetic abnormality in the lymphoma may show no response to H. pylori eradication therapy.     

幽门螺杆菌感染与胃癌及癌前病变中P21蛋白的表达

 用LSAB免疫组化法，对20例谓癌、22例异型增生、30例肠化生及13例正常组织进行了P21蛋白表达的检测。结果发现，胃癌、异型增生和肠化生的P21阳性者分别为13例（65.0%）,12例（60.0%）,11例（36.6%）,正常组织全部阴性；三种组织中，HP阳性病人的P21阳性率为41.6%（30/72）,明显高于HP阴性病人的8.3%（6/72）,有显着差别（P<0.01）.说明HP感染与P21过度表达存在着明显的相关性。提示HP感染可能通过ras癌基因的突变而参予致癌作用。