Causal role of Helicobacter pylori infection in gastric cancer

Gastric cancer is the second most frequent cancer in the world, accounting for a large proportion of all cancer cases in Asia, Latin America, and some countries in Europe. Helicobacter pylori(H pylori) is regarded as playing a specific role in the development of atrophic gastritis, which represents the most recognized pathway in multistep intestinal-type gastric carcinogenesis. Recent studies suggest that a combination of host genetic factors, bacterial virulence factors, and environmental and lifestyle factors determine the severity of gastric damage and the eventual clinical outcome of H pylori infection. The seminal discovery of H pylori as the leading cause of gastric cancer should lead to effective eradication strategies. Prevention of gastric cancer requires better screening strategies to identify candidates for eradication.     

Helicobacter pylori virulence factors--one part of a big picture

CONTEXT: At least half the world's population is infected with Helicobacter pylori, although only 10-20% of carriers develop gastric diseases, ranging from ulcer to MALT-lymphoma and adenocarcinoma (MALT is mucosa-associated lymphoid tissue). The clinical outcome of H pylori infection is determined by a complex interaction of environmental influences and host and microbial virulence factors. H pylori genotypes carrying the babA2 gene, encoding a bacterial adhesin mediating interaction with gastric epithelial cells, have enhanced pathogenicity. Moreover, coexistence of babA2 with other bacterial virulence factors further worsens clinical outcomes. STARTING POINT: To further elucidate the clinical relevance of babA2-genopositive H pylori strains, Carlo-Frederico Zambon and colleagues analysed the association of babA2 genotypes with gastritis, gastroduodenal ulcer disease, or intestinal metaplasia in 167 infected Italian individuals. The coexistence of babA2 with other potentially disease-related H pylori genes, such as cagA, vacA, or oipA, correlated with clinical outcome. 36% of H pylori strains were babA2(-) genopositive, and abundance of babA2 was associated with the genomic presence of the other potential virulence-factor genes. H pylori strains carrying babA2, cagA, and the vacA genotype s1m1 were associated with the highest risk of developing intestinal metaplasia, whereas this condition was rarely (<10%) associated with strains with a cagA-, babA2-, vacA s2m2 genotype. Whilst the risk of developing more serious gastric lesions increased as the number of virulence factor genes accumulated in a given H pylori strain, there was no indication of any one specific bacterial gene-pattern being associated with a particular clinical disease. WHERE NEXT? Identifying the factors responsible for the enhanced pathogenicity of H pylori leading to development of life-threatening diseases in a subset of infected individuals is a mandatory task for the future. Identification of virulence-associated H pylori genes and investigation of their clinical relevance in large prospective studies will help to define such strains with increased pathogenicity. The value of H pylori genotypes as predictors of disease outcome is limited, because the pathogenic impact of bacterial virulence factors is greatly influenced by coexisting environmental and host factors.     

Eradication of H pylori for the prevention of gastric cancer

Infection with H pylori is the most important known etiological factor associated with gastric cancer. While colonization of the gastric mucosa with H pylori results in active and chronic gastritis in virtually all individuals infected, the likelihood of developing gastric cancer depends on environmental, bacterial virulence and host specific factors. The majority of all gastric cancer cases are attributable to H pylori infection and therefore theoretically preventable. There is evidence from animal models that eradication of H pylori at an early time point can prevent gastric cancer development. However, randomized clinical trials exploring the prophylactic effect of H pylori eradication on the incidence of gastric cancer in humans remain sparse and have yielded conflicting results. Better markers for the identification of patients at risk for H pylori induced gastric malignancy are needed to allow the development of a more efficient public eradication strategy. Meanwhile, screening and treatment of H pylori in first-degree relatives of gastric cancer patients as well as certain high-risk populations might be beneficial.     

Helicobacter pylori virulence genes

Helicobacter pylori(H.pylori)is one of the most important human pathogens,infecting approximately half of the global population.Despite its high prevalence,only a subset of H.pylori infected individuals develop serious gastroduodenal pathology.The pathogenesis of H.pylori infection and disease outcome is thus thought to be mediated by an intricate interplay between host,environmental and bacterial virulence factors.H.pylori has adapted to the harsh milieu of the human stomach through possession of various virulence genes that enable survival of the bacteria in the acidic environment,movement towards the gastric epithelium,and attachment to gastric epithelial cells.These virulence factors enable successful colonization of the gastric mucosa and sustain persistent H.pylori infection,causing chronic inflammation and tissue damage,which may eventually lead to the development of peptic ulcers and gastric cancer.Numerous studies have focused on the prevalence and role of putative H.pylori virulence genes in disease pathogenesis.While several virulence factors with various functions have been identified,disease associations appear to be less evident,especially among different study populations.This review presents key findings on the most important H.pylori virulence genes,including several bacterial adhesins and toxins,in children and adults,and focuses on their prevalence,clinical significance and potential relationships.     

Helicobacter pylori infection and the pathogenesis of gastric cancer: A paradigm for host–bacterial interactions

Helicobacter pylori infection is the most important acquired risk factor for gastric cancer. The infection initiates a chronic inflammatory process that eventually alters the physiology of the gastric environment and leads to achlorohydria. Gastric atrophy may be part of this process but cancer can arise without this precursor. The net effect of decades of inflammation is the establishment of a milieu awash with pro-inflammatory cytokines and characterized by the activation of signalling pathways that cross-talk between inflammation and carcinogenesis. Many of the factors involved in chronic inflammation play a dual role in the process-promoting neoplastic progression but also facilitating cancer prevention. H. pylori bacterial virulence factors as well as host genetic factors play a major role in orchestrating the increased risk of cancer. The study of such host-bacterial interaction is key to uncovering the molecular and cellular pathways involved and will ultimately lead to developing preventive and therapeutic strategies against this global killer.     

Geographic differences and the role of cagA gene in gastroduodenal diseases associated with Helicobacter pylori infection.

Helicobacter pylori (H. pylori) is the major causal agent of gastritis, peptic ulcer and gastric cancer. Several bacterium genes seem to be involved in the pathogenicity mechanism. One of them, the cagA gene, has been extensively studied and characterized. In this article we have carried out a study of characteristics and genetic variability of cagA gene in different geographic areas of the world. At the same time, we have summarized several studies that evaluate possible relation of cagA with gastroduodenal diseases associated by H. pylori infection. In our study we found that the presence of the cagA gene has been confirmed in more than 60% H. pylori strains distributed throughout the world. The prevalence of cagA genotype is of 65.4% in gastritis patients, 84.2% in patients with peptic ulcer and 86.5% in those with gastric cancer. It shows a high genetic variability of cagA associated with gastroduodenal diseases that could serve as a virulence marker in H. pylori infected subjects. However, the high prevalence of H. pylori cagA positive strains in some geographic areas does not confirm the strong association between cagA and virulence of strains as described in other countries. Nowadays, cagA gene is considered as a marker for the presence of cag pathogenicity island (cag-PAI) in H. pylori genoma. This region contains several genes that has been involved with the production of cytokines that results in an increased inflammation of host gastric mucosa, but its function is unknown. Probably, others bacterium factors, such as susceptibility host and environmental cofactors could influence in the risk of developing different gastroduodenal diseases associated with H. pylori infection.     

Helicobacter pylori in Gastric Malignancies

Helicobacter pylori infection remains common worldwide and is significantly associated with gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT)lymphoma. This article reviews recent developments in the field of H. pylori with an emphasis on mechanisms of carcinogenesis, and the bacterial, environmental and host factors that may alter risk of developing gastric cancer or gastric MALT lymphoma. The topic of eradication of H. pylori to prevent the development of malignancy and the possibility of a vaccine against H. pylori are also explored.     

Can gastric cancer be prevented by Helicobacter pylori eradication?

Helicobacter pylori infection always causes chronic gastritis and triggers several gastroduodenal pathologies ranging from peptic ulcer disease to gastric cancer. It is well established that H. pylori eradication decreases the incidence of gastroduodenal ulcer and its recurrence. However, despite being accepted as the critical risk factor for gastric cancer, there is no conclusive evidence that H. pylori eradication decreases the incidence of gastric cancer. Bacterial virulence characteristics, as well as genetic predisposition of the host in conjunction with certain environmental conditions, are the major factors which influence the development of gastric cancer. Preclinical and clinical data suggest that reversibility of precancerous lesions (atrophic gastritis and intestinal metaplasia) is possible in some patients after H. pylori eradication. Since neoplastic lesions do not progress - or even regress in some cases - after H. pylori eradication, eradication therapy should be considered even in patients with precancerous lesions. Nonetheless, progression of atrophic gastritis and intestinal metaplasia into cancer has been also demonstrated in patients after H. pylori eradication, suggesting that there might be a point of no return where genetic changes have already happened and are irreversible despite elimination of the triggering carcinogen (H. pylori). At the present time the clinical decision to treat a patient is based on established risk profiles. A general screen-and-treat policy, although desirable, currently awaits a less complex treatment regimen.     

What exists beyond cagA and vacA? Helicobacter pylori genes in gastric diseases

Helicobacter pylori(H. pylori) infection is present in more than half the world's population and has been associated with several gastric disorders, such as gastritis, peptic ulceration, and gastric adenocarcinoma.The clinical outcome of this infection depends on host and bacterial factors where H. pylori virulence genes seem to play a relevant role. Studies of cag A and vac A genes established that they were determining factors in gastric pathogenesis. However, there are gastric cancer cases that are cag A-negative. Several other virulence genes have been searched for, but these genes remain less well known that cag A and vac A. Thus, this review aimed to establish which genes have been suggested as potentially relevant virulence factors for H. pylori-associated gastrointestinal diseases. We focused on the cag-pathogenicity island, genes with adherence and motility functions, and ice A based on the relevance shown in several studies in the literature.     

The inflammatory and immune response to Helicobacter pylori infection

Lifelong Helicobacter pylori infection and its associated gastric inflammation underlie peptic ulceration and gastric carcinogenesis. The immune and inflammatory responses to H. pylori are doubly responsible: gastric inflammation is the main mediator of pathology, and the immune and inflammatory response is ineffective, allowing lifelong bacterial persistence. However, despite inducing gastric inflammation, most infections do not cause disease, and bacterial, host and environmental factors determine individual disease risk. Although H. pylori avoids many innate immune receptors, specific virulence factors (including those encoded on the cag pathogenicity island) stimulate innate immunity to increase gastric inflammation and increase disease risk. An acquired T helper 1 response upregulates local immune effectors. The extent to which environmental factors (including parasite infection), host factors and H. pylori itself influence T-helper differentiation and regulatory T-cell responses remains controversial. Finally, effective vaccines have still not been developed: a better understanding of the immune response to H. pylori may help.     

Mechanisms of disease: Helicobacter pylori-related gastric carcinogenesis--implications for chemoprevention

Gastric adenocarcinoma is the second most common cause of cancer-related mortality worldwide. Infection with Helicobacter pylori is the single most common cause of adenocarcinoma of the distal stomach. Cancer risk is believed to be related to differences among H. pylori strains and inflammatory responses governed by host genetics. In particular, specific interactions between host factors that modulate the response to the infection, and bacterial virulence factors that can directly cause tissue damage seem to have a major pathogenic role in the development of gastric cancer. In addition, environmental factors can modify key growth signaling pathways within the gastric mucosa, which leads to the alteration of epithelial cell growth. Preventive strategies represent the most promising means of decreasing cancer risk, and must be aimed at the control of H. pylori infection, improvement of environmental conditions, and the identification of subjects who are genetically predisposed to the development of cancer in response to H. pylori infection. Understanding the intracellular signaling pathways that are specifically affected by H. pylori and that promote phenotypic and genotypic changes that might ultimately progress to malignant transformation could enable physicians to focus eradication therapy appropriately and design interventions targeted at the molecular level to prevent the development of gastric cancer.     

Diet, Hpylori infection and gastric cancer： Evidence and controversies

Despite decreasing incidence and mortality rates, gastric cancer (GC) still remains the fourth most common cancer and the second most common cause of cancer-related deaths worldwide. Due to the limited treatment options, at present, prevention is likely to be the only effective means of controlling this disease. The success of a prevention strategy depends upon the understanding of etiological and pathogenic mechanisms underlying gastric carcinogenesis. The etiology of GC is multi-factorial, however, in the recent years, mounting evidence suggests that environmental factors play a key role. The most important environmental factors implicated in the pathogenesis of GC are diet and H pylori infection. Thus, modifications in lifestyle and dietary habit associated with eradication of H pylori infection could hypothetically represent the most promising potential targets for GC prevention. In this review we will address the evidence and the controversies on the role of these agents in noncardia GC by focusing on retrospective and prospective observational studies and interventional trials.     

Helicobacter pylori infection as a model for gastrointestinal immunity and chronic inflammatory diseases

Approximately 50% of humanity is infected with Helicobacter pylori. It is a life-long infection that elicits a marked host inflammatory response; however, natural infection fails to yield protective immunity. Rather than providing protection, the chronic inflammatory response associated with natural infection contributes to tissue damage and the pathogenesis of gastroduodenal disease, including atrophic gastritis, peptic ulcer, and gastric cancer. While bacterial factors are important triggers of inflammation, many subjects infected with strains bearing putative virulence factors remain free from disease. Recent genetic studies have implicated the host's immune and inflammatory responses, suggesting that disease results from an interaction between bacterial and environmental factors in genetically susceptible hosts. Other digestive diseases, including celiac disease and inflammatory bowel disease, mimic this paradigm, where it appears that luminal triggers only manifest disease in subjects with the right combination of host and environmental factors. Since infection with H. pylori is relatively common, it is possible to study the impact of a specific etiologic agent on the pathogenesis of disease in humans. This approach has illuminated the complexity of the pathogenic mechanisms, but the advances achieved to date may provide some hints regarding the pathogenesis of chronic inflammatory diseases elsewhere in the digestive tract.     

Clinical relevance of Helicobacter pylori vacA and cagA genotypes in gastric carcinoma

Helicobacter pylori infection is the major etiological factor of gastric carcinoma. This disease is the result of a long, multistep, and multifactorial process, which occurs only in a small proportion of patients infected with H. pylori. Gastric carcinoma development is influenced by host genetic susceptibility factors, environmental factors, and H. pylori virulence. H. pylori is genetically highly variable, and variability that affects H. pylori virulence factors may be useful to identify strains with different degrees of pathogenicity. This review will focus on VacA and CagA that have polymorphic regions that impact their functional properties. The characterization of H. pylori vacA and cagA-associated could be useful for identifying patients at highest risk of disease, who could be offered H. pylori eradication therapy and who could be included in programs of more intensive surveillance in an attempt to reduce gastric carcinoma incidence.     

Gastric cancer: laboratory bench to clinic

Gastric cancer is the second most common cause of cancer-related mortality worldwide and the 14th overall cause of death. Detection of disease usually occurs at an advanced stage and overall survival rates for gastric cancer are poor. Our current model for gastric cancer progression clearly maintains Helicobacter infection as the primary inducer of gastric metaplastic and neoplastic disease. Helicobacter pylori is a ubiquitous organism, infecting more than half the world's population. It has been suggested that this infection directly contributes to the formation of gastric cancer in up to 80% of cases; however, gastric malignancy develops in only a subset (< 1%) of infected patients. Therefore, predisposition to Helicobacter-associated gastric cancer is most likely multifactorial, including the interaction of bacterial, host and environmental components. Our understanding of how the organism interacts with the gastric mucosa and synergizes with dietary and other environmental factors to induce malignant mucosal changes is evolving. Indeed, H. pylori has direct effects on the gastric mucosa, but the major factor in disease progression appears to be a robust host Th1 immune response in the setting of a permissive environment. In combination, these factors predispose to the formation of atrophy, metaplasia and gastric cancer. Understanding the interaction of the bacterium with the host and the environment can potentially identify patients most at risk. Identifying potentially removable factors (in addition to H. pylori infection) in the acquisition and progression of neoplastic disease may provide targets for early intervention and prevention strategies.     

胃幽门螺杆菌感染与抑癌基因失活的关系

目的探讨胃癌及癌前病变组织中幽门螺杆菌(H.pylori)感染与抑癌基因失活间的相互关系.方法运用DNA-PCR技术检测H.Pylori感染,采用PCR-RFLP,PCR-SSCP,RT-PCR及免疫组化技术分析182例胃癌及癌前病变及正常胃粘膜中抑癌基因APC,MCC,DCC,YNZ22及p53基因的杂合缺失、突变、mRNA及蛋白异常表达.结果胃癌及癌前病变组织中H.pylori的感染率(IM61.7%,Dys 63.3%,GC 42.3%)显著高于正常胃粘膜(17.5%,P＜0.05).但胃癌及癌前病变间H.pylori感染率无显著差别(P＞0.05),胃肠两型胃癌中H.pylori感染率分别为47.1%及42.2%,两者无显著差别(P＞0.05).胃癌及癌前病变组织中存在多种抑癌基因失活.H.pylori感染与癌前病变-肠化生中APC基因异常蛋白表达有关(Hp+43.2%vsHp-13.0%,P＜0.05).胃癌组织H.pylori感染阳性组中APC基因突变(50.0%)及蛋白表达(63.6%)、p53基因蛋白表达率(59.1%)显著高于阴性组(vs16.7%,P＜0.05;vs30.0%,P＜0.01;vs20.0%,P＜0.01).结论幽门螺杆菌感染及多种抑癌基因失活可能与胃癌的发生发展相关,H.pylori感染与APC,p53基因失活可能相关.     

宿主因素与幽门螺杆菌感染结局的研究

幽门螺杆菌（H．pylori）感染可导致不同的l艋床结局。H．pylori细菌毒力因素和宿主遗传易感性与胃癌相关。本文论述了H．pylori毒力因子、宿主基因多态性对主要胃病表型与不同l临床结局的影响。