From Helicobacter pylori infection to gastric cancer: Current evidence on the immune response

Gastric cancer (GC) is the result of a multifactorial process whose main components are infection by Helicobacter pylori (H. pylori), bacterial virulence factors, host immune response and environmental factors. The development of the neoplastic microenvironment also depends on genetic and epigenetic changes in oncogenes and tumor suppressor genes, which results in deregulation of cell signaling pathways and apoptosis process. This review summarizes the main aspects of the pathogenesis of GC and the immune response involved in chronic inflammation generated by H. pylori.     

Lack of association between Helicobacter pylori infection and oral lichen planus

Oral lichen planus is a premalignant chronic inflammatory mucosal disorder with unknown etiology. It is a multifactorial disease and in addition to genetic background, infections, stress, drug reactions are suggested as risk factors. Helicobacter pylori which is involved in development of many gastrointestinal lesions may also be implicated in oral lichen planus induction. This is of clear importance for cancer prevention and the present study was performed to determine any association between H. pylori infection and oral lichen planus in southwestern Iran. Anti H. pylori IgG levels were determined in 41 patients and 82 sex-age matched controls. The results showed no association between H. pylori infection and oral lichen planus (51% in patients vs. 66% in control). or any of its clinical presentations.     

Gastric cancers in Finnish patients after cure of Helicobacter pylori infection: A cohort study

Helicobacter pylori infection is associated with gastric cancer. A total of 97% of the infected subjects have elevated levels of H. pylori antibodies. The antibody titers have been shown to decline rapidly (40–60% within 4–12 months) only after successful eradication therapy. We allocated 26,700 consecutive patients tested during 1986–1998 for H. pylori antibodies to 3 subcohorts: seropositive patients with rapidly falling antibody titers (Hp+CURED, n = 3,650), seropositive patients where no serological information indicating cure was obtained (Hp+NoInfo, n = 11,638) and seronegative patients (Hp–, n = 11,422). In the subcohorts, the standardised incidence ratios (SIRs) with 95% confidence intervals (CI) were defined for subsequent cancers of stomach, pancreas, colon, rectum, breast and prostate separately and for all cancers except stomach combined. The mean follow‐up time was 10.1 years and the number of gastric cancers was 72. For the Hp+CURED, the SIR for gastric cancers for the first 5 follow‐up years was 1.62 but decreased from the sixth follow‐up year thereon to 0.14 (CI: 0.00–0.75). Likewise, the risk ratio, defined in a Poisson regression analysis using the Hp+NoInfo group as the reference, decreased from 1.60 to 0.13 (CI: 0.02–1.00, p = 0.049). The SIR for Hp– was not significantly higher than that for Hp+NoInfo for any of the cancers analysed. To conclude, cured H. pylori infection led to a significantly decreased incidence of gastric cancers from the sixth follow‐up year. Advanced atrophic gastritis would be a plausible contributor to the elevated SIR in elderly Hp– patients.     

胃肠道淋巴瘤Survivin表达与幽门螺杆菌感染的关系及意义

目的: 探讨Survivin基因在胃肠道B细胞淋巴瘤(BCL)中的表达及其与幽门螺杆菌(Helicobacter pylori,HP)感染的关系。 方法: 用免疫组化法检测56例胃肠道BCL和30例正常胃肠组织中Survivin的表达,并用碱性品红染色法检测胃肠道BCL及正常对照组HP感染情况。 结果: 胃BCL中Survivin的表达阳性率46.67%(14/30),肠BCL阳性率42.31%(11/26),两组对比差异无显著性意义(P>0.05);总的胃肠道BCL Survivin表达阳性率44.64%(25/56),在正常胃肠组织均无表达,两组表达阳性率对比差异有显著性(P<0.01);低度恶性胃肠BCLSurvivin表达阳性率20.83%(5/24),高度恶性胃肠BCL阳性率65.63%(21/32),两组阳性率对比差异有显著性(P<0.01)。胃BCLHP检测阳性率46.67%(14/30),肠BCL30.77%(8/26),两组阳性率对比,差异无显著性(P>0.05);56例胃肠道BCLHP阳性率39.29%(22/56),正常对照组13.33%(4/30),两组阳性率对比,差异有显著性意义(P<0.05);MALT(mu-cosa—associated lymphoid tissue,MALT)淋巴瘤HP阳性率66.67%(16/24),非MALT淋巴瘤阳性率18.75%(6/32),两组对比差异有显著性(P<0.01);胃肠BCLSurvivin阳性表达与HP感染有相关性(P<0.05)。 结论: Survivin基因在胃肠道B细胞淋巴瘤中表达上调,而且Survivin表达与HP感染有显著性相关,提示该基因及HP感染对胃肠淋巴瘤发生、发展起重要作用。     

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.     

Association of Helicobacter pylori infection with chronic atrophic gastritis: Meta-analyses according to type of disease definition

Helicobacter pylori is a major risk factor for chronic atrophic gastritis (CAG). A large variety of definitions of CAG have been used in epidemiologic studies in the past. The aim of this work was to systematically review and summarize estimates of the association between H. pylori infection and CAG according to the various definitions of CAG. Articles on the association between H. pylori infection and CAG published until July 2007 were identified. Separate meta-analyses were carried out for studies defining CAG based on gastroscopy with biopsy, serum pepsinogen I (PG I) only, the pepsinogen I/pepsinogen II ratio (PG I/PG II ratio) only, or a combination of PG I and the PG I/PG II ratio. Numbers of identified studies and summary odds ratios (OR) (95% confidence intervals) were as follows: gastroscopy with biopsy: n = 34, OR = 6.4 (4.0-10.1); PG I only: n = 13, OR = 0.9 (0.7-1.2); PG I/PG II ratio: n = 8, OR = 7.2 (3.1-16.8); combination of PG I and the PG I/PG II ratio: n = 20, OR = 5.7 (4.4-7.5). Studies with CAG definitions based on gastroscopy with biopsy or the PG I/PG II ratio (alone or in combination with PG I) yield similarly strong associations of H. pylori with CAG. The association is missed entirely in studies where CAG is defined by PG I only.     

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.     

Declining trends in prevalence of Helicobacter pylori infection by birth‐year in a Japanese population

Gastric cancer incidence and mortality have been decreasing in Japan. These decreases are likely due to a decrease in prevalence of Helicobacter pylori infection. Our aim was to characterize the trends in prevalence of H. pylori infection focused on birth‐year. We carried out a cross‐sectional study that included 4285 subjects who were born from 1926 to 1989. We defined H. pylori infection by the serum H. pylori antibody titer. Individuals having H. pylori infection and those with negative H. pylori antibody titer and positive pepsinogen test were defined as high‐risk individuals for gastric cancer. We estimated the birth‐year percent change (BPC) of the prevalence by Joinpoint regression analysis. The prevalence of H. pylori infection among the subjects born from 1927 to 1949 decreased from 54.0% to 42.0% with a BPC of −1.2%. It was followed by a rapid decline in those born between 1949 (42.0%) and 1961 (24.0%) with a BPC of −4.5%, which was followed by those born between 1961 (24.0%) and 1988 (14.0%) with a BPC of −2.1%. The proportion of high‐risk individuals for gastric cancer among the subjects born from 1927 to 1942 decreased from 62.0% to 55.0% with a BPC of −0.8%. A subsequent rapid declining trend was observed in those born between 1942 (55.0%) and 1972 (18.0%) with a BPC of −3.6%, and then it became stable. These remarkable declining trends in the prevalence of H. pylori infection by birth‐year would be useful to predict the future trend in gastric cancer incidence in Japan.     

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     

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。     

幽门螺杆菌感染与胰腺癌发病相关性的Meta分析

目的:探讨幽门螺杆菌(Helicobacter pylori,Hp)感染与胰腺癌发病的相关性。方法:收集1990年-2013年国内外公开发表的关于幽门螺杆菌感染与胰腺癌发病相关性的病例对照研究的文献,应用Review Manager4.2软件Meta分析,计算合并优势比（odd ratio,OR值）及OR值95％可信区间(confidence interval,CI),倒漏斗图法定性评价发表性偏倚。结果:共7篇相关文献入选,总样本量2641例,其中胰腺癌947例,对照组1694例,Meta分析得出幽门螺杆菌感染与胰腺癌发病合并OR值为1.40（95%CI为 1.04-1.89,Z=2.21,P=0.03）。本研究倒漏斗分析图形不对称,但经敏感性分析和计算失安全系数证明,发表性偏倚对结果有一定的影响。结论:幽门螺杆菌感染是胰腺癌发病的危险因素。     

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.     

幽门螺杆菌感染和环氧合酶-2表达在胃癌发生中的作用

目的探讨幽门螺杆菌 (Hp) 感染和环氧合酶-2(COX-2)表达在胃癌发生中的作用.方法 138例胃镜活检标本包括慢性非萎缩性胃炎30例,慢性萎缩性胃炎85例(其中伴有中度以上肠化生45例,中、重度异型增生12例),和胃癌23例.快速尿素酶试验和组织学改良Giemsa染色联合检测Hp,免疫组化检查COX-1和COX-2表达.结果胃癌的Hp阳性率为69.6%,显著高于慢性非萎缩性胃炎的36.7%(P<0.05).慢性非萎缩性胃炎、慢性萎缩性胃炎、肠化生、异型增生和胃癌的COX-2表达率分别为10.0%、37.6%、37.8%、41.7%和69.6%,而不同胃黏膜病变中COX-1表达无明显差异.慢性萎缩性胃炎、肠化生和异型增生中Hp阳性病例的COX-2表达显著高于Hp阴性病例(P<0.01).结论 Hp感染及其诱导的COX-2表达可能是胃癌发生的早期事件之一.     

幽门螺杆菌感染与长乐门区胃癌发生的关系

目的：探讨胃粘膜幽门螺杆菌(Helicobacter pylori,Hp)感染对细胞凋亡及EGFR、VEGF表达的影响,从而初步探讨HP感染与长乐市高发区胃癌发生的关系。方法：采用碱性品红染色法和血Hp抗体检测法检测Hp感染状况;原位末端标记法（TUNEL法）检测胃粘膜细胞凋亡指数;免疫组化S－P法检测胃粘膜EGFR及VEGF表达情况。结果：长乐市胃癌温室伦系列Hp现症感染率（Hp 率）为74．4％,以慢性萎缩性胃炎伴或不伴肠化（CAG－IM）组最高,为92．5％;细胞凋亡指数在CAG－IM组最高,为0．357,而胃癌组最低,为0．179;EGFR表达阳性率为51．35％,其中CAG－IM组阳性率最高,达75．05,慢性浅表性胃炎（CSG）组最低,为25．05,胃癌组为46．7％;VEGF在不典型增生（AH）组最低,为35．0％,在胃癌组最高,为65．0％,（P＜0．05）。VEGFg怼umP《0、05）。Hp感染使胃粘膜凋亡指数增高,EGFR表达增加,VEGF表达下降（P＜0．05）。结论:Hp感染与长乐市高发区胃癌发生相关,Hp感染影响了胃粘膜细胞EGFR、VEGF的表达及胃粘膜细胞的增生和凋亡,从而可能影响了胃癌演化系列发生、发展的动态过程。     

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.     

S期激酶相关蛋白2在幽门螺杆菌L型致胃癌中的作用

目的：研究S期激酶相关蛋白2（S-phase kinase associated protein 2,Skp2）在幽门螺杆菌L型（Helicobacter pylori L-form,Hp-L型）感染致胃癌中所起的作用。方法：将胃癌BGC-823细胞与Hp-L型以不同比例共培养,在倒置显微镜下观察细胞形态学变化,并应用原位杂交和免疫组化分别检测Skp2 mRNA和蛋白在胃癌BGC-823细胞中的表达情况。同时收集慢性萎缩性胃炎（CAG）、胃肠腺化生（GIM）、胃不典型增生（GED）、胃癌（GCa）标本各40例,以40例轻度慢性浅表性胃炎（CSG）作为对照。应用革兰染色和免疫组化检测Hp-L型在上述组织中的感染情况;并进一步检测Hp-L型阳性组织中Skp2 mRNA和蛋白的表达情况。结果：Hp-L型作用BGC-823细胞后,倒置显微镜观察到细胞分裂增多,出现明显的生长加速现象;原位杂交和免疫组化检测发现BGC-823细胞中Skp2 mRNA和蛋白表达阳性率随细菌浓度的增加和作用时间的延长而逐渐增加（P〈0.05）。Hp-L型阳性组织中的Skp2mRNA和蛋白的表达阳性率按CAG、GIM、GED、GCa的顺序逐渐增加,但仅GCa组与CSG组间的差异具有统计学意义（P〈0.05）。结论：Skp2在Hp-L型感染的胃癌前病变及胃癌中均明显升高,提示其在胃癌的发生及发展中起着重要作用。     

Global burden of gastric cancer attributable to Helicobacter pylori

We previously estimated that 660,000 cases of cancer in the year 2008 were attributable to the bacterium Helicobacter pylori (H. pylori), corresponding to 5.2% of the 12.7 million total cancer cases that occurred worldwide. In recent years, evidence has accumulated that immunoblot (western blot) is more sensitive for detection of anti‐H. pylori antibodies than ELISA, the detection method used in our previous analysis. The purpose of this short report is to update the attributable fraction (AF) estimate for H. pylori after briefly reviewing new evidence, and to reassess the global burden of cancer attributable to H. pylori. We therefore reviewed the literature for studies comparing the risk of developing non‐cardia gastric cancer (NCGC) in cases and controls, using both ELISA and multiple antigen immunoblot for detection of H. pylori. The results from prospective studies were combined, and the new pooled estimates were applied to the calculation of the AF for H. pylori in NCGC, then to the burden of infection‐related cancers worldwide. Using the immunoblot‐based data, the worldwide AF for H. pylori in NCGC increased from 74.7% to 89.0%. This implies approximately 120,000 additional cases of NCGC attributable to H. pylori infection for a total of around 780,000 cases (6.2% instead of 5.2% of all cancers). These updated estimates reinforce the role of H. pylori as a major cause of cancer.     

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.