Helicobacter pylori in gastric carcinogenesis

Gastric cancer still is a major concern as the third most common cancer worldwide, despite declining rates of incidence in many Western countries. Helicobacter pylori (H. pylori) is the major cause of gastric carcinogenesis, and its infection insults gastric mucosa leading to the occurrence of atrophic gastritis which progress to intestinal metaplasia, dysplasia, early gastric cancer, and advanced gastric cancer consequently. This review focuses on multiple factors including microbial virulence factors, host genetic factors, and environmental factors, which can heighten the chance of occurrence of gastric adenocarcinoma due to H. pylori infection. Bacterial virulence factors are key components in controlling the immune response associated with the induction of carcinogenesis, and cagA and vacA are the most well-known pathogenic factors. Host genetic polymorphisms contribute to regulating the inflammatory response to H. pylori and will become increasingly important with advancing techniques. Environmental factors such as high salt and smoking may also play a role in gastric carcinogenesis. It is important to understand the virulence factors, host genetic factors, and environmental factors interacting in the multistep process of gastric carcinogenesis. To conclude, prevention via H. pylori eradication and controlling environmental factors such as diet, smoking, and alcohol is an important strategy to avoid H. pylori-associated gastric carcinogenesis.     

Helicobacter pylori associated Asian enigma: Does diet deserve distinction?

Helicobacter pylori(H. pylori) is one of the most widespread infections in humans worldwide that chronically infects up to 50% of the world’s population. The infection is involved in the pathogenesis of chronic active gastritis, peptic ulcer, mucosa-associated lymphoid tissue lymphoma and gastric cancer, therefore, it has been classified as class Ⅰ definite carcinogen by the World Health Organization. Despite the established etiological role of H. pylori, its actual distribution and association with related diseases is controversial and there is a large intercountry variation especially among Asian countries. H. pylori infection is more frequent in developing countries like India, Pakistan, and Bangladesh as compared to developed Asian countries like Japan, China and South Korea. However, the frequency of gastric cancer is comparatively lower in India, Pakistan, and Bangladesh with that of Japan, China and South Korea. Such phenomenon of clinical diversity, defined as enigma, is judged by genetic variability of the infecting H. pylori strains, differences in the host genetic background in various ethnic groups, and environmental factors such as dietary habits. Most of the studies have so far focused on the bacterial factor while environmental issues, including dietary components, were not given due attention as one of the factors related with H. pylori associated gastric carcinogenesis. The dietary factor has been suggested to play an important role in H. pylori related carcinogenesis, and in this respect several studies have corroborated the intake of various dietary components as modulatory factors for gastric cancer risk. In this review, such studies, from in vitro experiments to clinical trials, are being focused in detail with respect to enigma associated with H. pylori. It may be conceivably concluded from the available evidence that dietary factor can be a game changer in the scenario of Asian enigma, particularly in high risk population infected with virulent H. pylori strains, however further affirmation studies are desperately needed to achieve conclusive outcomes.     

Polymorphisms in mucin genes in the development of gastric cancer

Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. In areas of high prevalence, such as Japan, South Korea and China, most cases of GC are related to Helicobacter pylori (H. pylori), which involves well-characterized sequential stages, including infection, atrophic gastritis, intestinal metaplasia, dysplasia, and GC. Mucins are the most abundant high-molecular-weight glycoproteins in mucus, which is the first line of defense and plays a major role in blocking pathogenic factors. Normal gastric mucosa shows expression of MUC1, MUC5AC and MUC6 that is specific to cell type. However, the specific pattern of MUC1, MUC5AC and MUC6 expression is changed in gastric carcinogenesis, accompanied by de novo expression of secreted MUC2. Recent studies have provided evidence that variations in these mucin genes affect many steps of GC development, such as H. pylori infection, and gastric precancerous lesions. In this review, we focus on studies of the association between polymorphisms in mucin genes and development of GC. This information should be helpful for the early detection, surveillance, and treatment of GC.     

Helicobacter pylori virulence factors in gastric carcinogenesis

Helicobacter pylori infection is the most important risk factor in the development of non-cardia gastric adenocarcinoma; host genetic variability and dietary co-factors also modulate risk. Because most H. pylori infections do not cause cancer, H. pylori heterogeneity has been investigated to identify possible virulence factors. The strongest candidates are genes within the cag (cytotoxin-associated antigen) pathogenicity island, including the gene encoding the CagA protein, as well as polymorphic variation in the VacA vacuolating exotoxin and the blood group antigen binding adhesin BabA. Improved understanding of the pathogenesis of H. pylori-associated gastric cancer may improve risk stratification for prevention and therapy.     

Correlation of Helicobacter pylori and interleukin-8 mRNA expression in high risk gastric cancer population prediction

AIM: To evaluate (1) the association of the Helicobacter pylori (H. pylori) test and interleukin-8 (IL-8) mRNA expression alone and the severity of gastric cancer (GC); (2) the association of both tests were added to patients'' characteristics to identifli Thai suspected patients of gastric cancer who would receive the most benefit; and (3) diagnostic value of levels of IL-8 mRNA expression for gastric cancer.METHODS: A cross-sectional analytical study was completed with 220 patients with 86 GC patients who underwent endoscopy with gastric surgery divided into non-metastasis and metastasis groups, and 134 patients with benign lesions who underwent endoscopic examination, at the Gastrointestinal Surgery and Endoscopy Unit, Chiang Mai University Hospital between 2006 and 2010. Of 220 patients, 86 cases of diagnosed gastric adenocarcinoma were in an advanced stage and 134 cases were non-cancer patients.RESULTS: The IL-8 mRNA expression showed predominant association with advanced GC when compared to H. pylori infection alone [OR (95%CI); 0.86 (0.49-1.53) vs 5.44 (3.08-9.62)] when including the patients’ characteristics the highest of the area under the receiver operating characteristic curves (AuROC) of the model were males older than 40 years of age [AuROC (95%CI); 0.81 (0.75-0.86)]. However, preliminary testing for diagnostic indices of four cut-off points of IL-8 mRNA expression to predict the severity of GC cases found an increasing suboptimal trend from the likelihood ratio of positive to differentiate the severity in the GC group. The IL-8 mRNA expression showed a predominant association with GC when compared to H. pylori infection, especially in males older than 40 years of age who may benefit most from this test.CONCLUSION: The future research of IL-8 mRNA expression to predict severity in the gastric cancer group should be warranted.     

H. pylori Infection,Inflammation and Gastric Cancer

Introduction

A strong association between chronic infection, inflammation, and cancer has been suggested.

Discussion

Helicobacter pylori, a microaerophilic gram negative bacterium, infects about half the world’s population. It has been defined as a definitive carcinogen in the pathogenesis of gastric cancer. H. pylori evades the host immune responses and persists in the stomach leading to gastritis gastric atrophy and sometimes gastric cancer.

Conclusion

Chronic H. pylori infection causes gastric cancer via two mechanisms: the presence of virulence factors and the induction of chronic inflammation which ultimately leads to neoplastic transformation.     

Helicobacter pylori bacteria alter the p53 stress response via Erk-HDM2 pathway

H. pylori infection is the strongest known risk factor for gastric cancer. Inhibition of host tumor suppressor mechanisms by the bacteria underlies the development of this disease. Among the tumor suppressors affected by H. pylori are p53 and E-cadherin, which inhibition has been shown to increase the risk of gastric cancer. In this report, we investigated the interaction between E-cadherin and p53 in H. pylori-infected cells. We found that downregulation of E-cadherin leads to cellular stress and activation of p53. In the setting of H. pylori infection, this mechanism, however, is disrupted. We found that although co-culture of gastric epithelial cells with H. pylori led to downregulation of E-cadherin and cellular stress, it resulted in inhibition of p53, which is mediated by intracellular Erk kinases and HDM2 protein induced by H. pylori. Experimental inhibition of HDM2/p53 interactions restored p53 activity, and decreased survival of infected cells. Collectively, our results revealed that regulation of p53 and E-cadherin is tightly linked through the p53 stress response mechanism that is inhibited by H. pylori via activation of Erk1/2-HDM2-p53 pathway leading to survival of damaged cells. This might be advantageous to the bacteria but may increase the cancer risk.     

Late reactivation of sonic hedgehog by Helicobacter pylori results in population of gastric epithelial cells that are resistant to apoptosis: Implication for gastric carcinogenesis

As much as that a disturbance of tissue homeostasis through dysregulated apoptosis is generally associated with carcinogenesis, gastric carcinogenesis after Helicobacter pylori infection could be the accumulated consequence of imbalances between apoptosis and proliferation. Since sonic hedgehog (Shh) has been reported to play versatile roles in various tumorigenesis, we hypothesized that late reactivation of sonic hedgehog by H. pylori infection results in population of gastric epithelial cells that are resistant to apoptosis. The Resistant Clones against H. pylori-induced Apoptosis (RCHA) were established and maintained up to 19th cell passages, during which the serial changes of Shh expression were measured. Apoptosis was measured in N-Shh over-expressed stable cell lines and compared with parent cell line after either infected with H. pylori or treated with cyclopamine. For clinical relevance, the expressions of Shh were compared in tissues from gastric adenoma or adenocarcinoma according to H. pylori infection. Longer passages of RCHA after H. pylori infection, the higher expressions of Shh, suggesting RCHA was associated with the reactivation of Shh. Significant decrement in subG1 phase of cell cycle and attenuated executions of apoptosis after H. pylori infection in cells of Shh overexpression, whereas either Shh siRNA or cyclopamine increased the H. pylori-induced cytotoxicity and significantly abrogated anti-apoptotic actions imposed by Shh. Significantly higher expressions of Shh were seen in H. pylori-associated gastric cancers than H. pylori-not associated gastric cancer. Late reactivation of sonic hedgehog by H. pylori infection results in population of gastric epithelial cells that are resistant to apoptosis and imposes proliferative changes under the background of atrophic gastritis, providing the carcinogenic basis.     

Activation of CD3+ T cells by Helicobacter pylori DNA vaccines in potential immunotherapy of gastric carcinoma

Most of gastric carcinoma (GC) is attributed to infection by Helicobacter pylori (H. pylori) but there is increasing evidence that the positive H. pylori status correlates with better prognosis in GC. The H. pylori-induced cellular immune response may suppress cancer and in this work, recombinant pcDNA3 plasmids encoding various fragments of H. pylori virulence genes of cagA, vacA and babA are constructed and combined into groups to immunize BALB/c mice. The activated splenic CD3⁺ T cells are purified and the anticancer effects are investigated in vitro and in vivo. The H. pylori DNA vaccines induce a shift in the response from Th1 to Th2 that mimicks the immune status in patients of GC with chronic H. pylori infection. The stimulated CD3⁺ T cells inhibit the growth of human GC cells in vitro and adoptive transfusions of the CD3⁺ T cells suppress the growth of GC xenograft in vivo. The effects may be caused by the larger ratios of infiltrated CD8⁺/CD4⁺ T cells, reduced infiltration of regulatory FOXP3⁺ T cells, and enhanced apoptosis induced by upregulation of Caspase-9/Caspase-3 and downregulation of Survivin. Our results reveal the potential immunotherapeutic value of H. pylori vaccine-activated CD3⁺ T cells in those with advanced GC.     

Salt intake and gastric cancer risk according to Helicobacter pylori infection, smoking, tumour site and histological type

Background:

Although salt intake is considered a probable risk factor for gastric cancer, relevant studies have provided heterogeneous results, and the magnitude of the association has not been accurately quantified.

Methods:

To quantify gastric cancer risk in relation to dietary salt exposure according to Helicobacter pylori infection status and virulence, smoking, tumour site, and histological type, we evaluated 422 gastric cancer cases and 649 community controls. Salt exposure was estimated in the year before the onset of symptoms through: sodium intake (estimated by a food frequency questionnaire (FFQ)); main food items/groups contributing to dietary sodium intake; visual analogical scale for salt intake preference; use of table salt; and duration of refrigerator ownership.

Results:

Comparing subjects with the highest with those with the lowest salt exposure (3rd vs 1st third), sodium intake (OR=2.01, 95% CI: 1.16–3.46), consumption of food items with high contribution to sodium intake (OR=2.54, 95% CI: 1.56–4.14) and salt intake evaluated by visual analogical scale (OR=1.83, 95% CI: 1.28–2.63) were associated with an increased gastric cancer risk. Subjects owning a refrigerator for >50 years had a lower risk for gastric cancer (OR=0.28, 95% CI: 0.14–0.57). These associations were observed regardless of H. pylori infection status and virulence, smoking, tumour site or histological type.

Conclusion:

Our results support the view that salt intake is an important dietary risk factor for gastric cancer, and confirms the evidence of no differences in risk according to H. pylori infection and virulence, smoking, tumour site and histological type.     

Helicobacter pylori-induced gastric inflammation and gastric cancer

Helicobacter pylori (H. pylori) infect over half of the world’s population. The prevalence of H. pylori infection and the predominant genotype of H. pylori virulence factors vary considerably across different geographical regions.     

Impact of alcohol drinking on gastric cancer development according to Helicobacter pylori infection status

Background:

Helicobacter pylori are major carcinogen of gastric cancer, but the associations among gastric cancer, H. pylori infection status, and alcohol consumption are not fully described. This study aimed to clarify how H. pylori infection status affects the association between alcohol consumption and gastric cancer risk.

Methods:

We selected 949 case–cohort participants from the 18 863 Korean Multi-center Cancer Cohort (KMCC) populations. Gastric cancer incidence inside and outside of the subcohort were 12 and 254 cases, respectively. Seropositivities for CagA, VacA, and H. pylori infection were determined by performing immunoblot assays. Weighted Cox regression models were used to calculate hazard ratios and 95% confidence intervals (CIs).

Results:

Relative to non-drinking, heavy drinking (⩾7 times a week), and binge drinking (⩾55 g alcohol intake per occasion) showed a 3.48-fold (95% CI, 1.13–10.73) and 3.27-fold (95% CI, 1.01–10.56) higher risk in subjects not previously infected by H. pylori. There was no significant association between drinking pattern and gastric cancer risk in H. pylori IgG seropositive subjects. An increased risk for gastric cancer in heavy- and binge-drinking subjects were also present in subjects not infected by CagA- or VacA-secreting H. pylori.

Conclusions:

Heavy and binge alcohol consumption is an important risk factor related to an increasing incidence of gastric cancer in a population not infected by H. pylori.     

The role of Helicobacter pylori in the pathogenesis of gastric malignancies

Helicobacter pylori is the world’s most common chronic bacterial infection, colonizing more than half of the population globally. Although all strains cause persistent gastric inflammation, most cases are asymptomatic; only 15% result in peptic ulcer disease and less than 2% of cases will develop gastric adenocarcinoma or the even rarer mucosa associated lymphoma (MALT). Considerable evidence implicates H. pylori in the pathogenesis of gastric malignancies-still a major burden in much of the world. Interactions between host factors, environmental factors and specific H. pylori constituents (or virulence factors) are important in determining the outcome of infection. Despite the relative ease of eradicating H. pylori with 1–2 week course of proton pump inhibitors and antibiotics in individuals, whether to actively seek occult H. pylori infection at the population level to attempt to prevent the burden of H. pylori-associated gastric malignancy remains surprisingly controversial.     

Early or late antibiotic intervention prevents Helicobacter pylori-induced gastric cancer in a mouse model

H. pylori infection causes gastritis, peptic ulcers and gastric cancer. Eradicating H. pylori prevents ulcers, but to what extent this prevents cancer remains unknown, especially if given after intestinal metaplasia has developed. H. pylori infected wild-type (WT) mice do not develop cancer, but mice lacking the tumor suppressor p27 do so, thus providing an experimental model of H. pylori-induced cancer. We infected p27-deficient mice with H. pylori strain SS1 at 6–8 weeks of age. Persistently H. pylori-infected WT C57BL/6 mice served as controls. Mice in the eradication arms received antimicrobial therapy (omeprazole, metronidazole and clarithromycin) either “early” (at 15 weeks post infection, WPI) or “late” at 45 WPI. At 70 WPI, mice were euthanized for H. pylori determination, histopathology and cytokine/chemokine expression. Persistently infected mice developed premalignant lesions including high-grade dysplasia, whereas those given antibiotics did not. Histologic activity scores in the eradication groups were similar to each other, and were significantly decreased compared with controls for inflammation, epithelial defects, hyperplasia, metaplasia, atrophy and dysplasia. IP-10 and MIG levels in groups that received antibiotics were significantly lower than controls. There were no significant differences in expression of IFN-γ, TNF-α, IL-1β, RANTES, MCP-1, MIP-1α or MIP-1β among the three groups. Thus, H. pylori eradication given either early or late after infection significantly attenuated gastric inflammation, gastric atrophy, hyperplasia, and dysplasia in the p27-deficient mice model of H. pylori-induced gastric cancer, irrespective of the timing of antibiotic administration. This was associated with reduced expression of IP-10 and MIG.     

The influence of cytokine gene polymorphisms on the risk of developing gastric cancer in patients with Helicobacter pylori infection

Background

Helicobacter pylori infection is the main cause of gastric cancer. The disease progression is influenced by the host inflammatory responses, and cytokine single nucleotide polymorphisms (SNPs) may have a role in the course of the disease. The aim of our study was to investigate proinflammatory cytokine polymorphisms, previously associated with the development of gastric cancer, in a Slovenian population.

Patients and methods.

In total 318 patients and controls were selected for the study and divided into three groups: (i) patients with gastric cancer (n = 58), (ii) patients with chronic gastritis (n = 60) and (iii) healthy control group (n = 200). H. pylori infection in patient groups was determined by serology, histology and culture. Four proinflammatory gene polymorphisms were determined (IL-1β, IL-1ra, TNF-α, TLR-4) in all subjects.

Results

We found a statistically significant difference between males and females for the groups (p = 0.025). Odds ratio (OR) for gastric cancer risk for females was 0.557 (95% confidence interval [CI]: 0.233–1.329) and for chronic gastritis 2.073 (95% CI: 1.005–4.277). IL-1B-511*T/T homozygous allele for cancer group had OR = 2.349 (95% CI: 0.583–9.462), heterozygous IL-1B-511*T had OR = 1.470 (95% CI: 0.583–3.709) and heterozygotes in TNF-A-308 genotype for chronic gastritis had OR = 1.402 (95% CI: 0.626–3.139). Other alleles had OR less than 1.

Conclusions

We could not prove association between gastric cancer and chronic gastritis due to H. pylori in any cytokine SNPs studied in Slovenian population. Other SNPs might be responsible besides infection with H. pylori for the progression from atrophy to neoplastic transformation.     

Helicobacter pylori induces epithelial-mesenchymal transition in gastric carcinogenesis via the AKT/GSK3β signaling pathway

Helicobacter pylori (H. pylori) is a main risk factor for gastric cancer (GC). Epithelial-mesenchymal transition (EMT) is involved in the development and progression of H. pylori-associated GC. However, the exact molecular mechanism of this process remains unclear. The AKT/GSK3β signaling pathway has been demonstrated to promote EMT in several types of cancer. The present study investigated whether H. pylori infection induced EMT, and promoted the development and metastasis of cancer in the normal gastric mucosa, and whether this process was dependent on AKT activation. The expression levels of the EMT-associated proteins, including E-cadherin and N-cadherin, were determined in 165 gastric mucosal samples of different disease stages by immunohistochemical analysis. The expression levels of E-cadherin, N-cadherin, AKT, phosphorylated (p-)AKT (Ser473), GSK3β and p-GSK3β (Ser9) were further determined in H. pylori-infected Mongolian gerbil gastric tissues and cells co-cultured with H. pylori by immunohistochemical analysis and western blotting. The results indicated that the expression levels of the epithelial marker E-cadherin were decreased, whereas the expression levels of the mesenchymal marker N-cadherin were increased during gastric carcinogenesis. Their expression levels were associated with H. pylori infection. Furthermore, H. pylori infection resulted in downregulation of E-cadherin expression and upregulation of N-cadherin expression in Mongolian gerbils and GES-1 cells. In addition, an investigation of the associated mechanism of action revealed that p-AKT (Ser473) and p-GSK3β (Ser9) were activated in GES-1 cells following co-culture with H. pylori. Furthermore, following pretreatment of the cells with the AKT inhibitor VIII, the expression levels of E-cadherin, N-cadherin, p-AKT and p-GSK3β did not show significant differences between GES-1 cells that were co-cultured with or without H. pylori. The levels of p-AKT and p-GSK3β were increased in H. pylori-infected Mongolian gerbils. In conclusion, the present study demonstrated that H. pylori infection activated AKT and resulted in the phosphorylation and inactivation of GSK3β, which in turn promoted early stage EMT. These effects were AKT-dependent. This mechanism may serve as a prerequisite for GC development.     

Helicobacter pylori in the pathogenesis of gastric cancer and gastric lymphoma

Chronic gastric infection by the gram-negative bacterium Helicobacter pylori is strongly associated with the development of distal gastric carcinoma and gastric mucosal lymphoma in humans. Eradication of H. pylori with combination antibiotic therapy cures most cases of gastric lymphoma and slows progression to gastric adenocarcinoma. H. pylori promotes gastric neoplasia, principally via the induction of an intense gastric inflammatory response that lasts over decades. This persistent inflammatory state produces chronic oxidative stress and adaptive changes in gastric epithelial and immune cell pathobiology that in a minority of infected subjects eventually proceeds to frank neoplastic transformation.     

Advances in gastric cancer prevention

Gastric cancer is a multifactorial neoplastic pathology numbering among its causes both environmental and genetic predisposing factors. It is mainly diffused in South America and South-East Asia, where it shows the highest morbility percentages and it is relatively scarcely diffused in Western countries and North America. Although molecular mechanisms leading to gastric cancer development are only partially known, three main causes are well characterized: Helicobacter pylori (H. pylori) infection, diet rich in salted and/or smoked food and red meat, and epithelial cadherin (E-cadherin) mutations. Unhealthy diet and H. pylori infection are able to induce in stomach cancer cells genotypic and phenotypic transformation, but their effects may be crossed by a diet rich in vegetables and fresh fruits. Various authors have recently focused their attention on the importance of a well balanced diet, suggesting a necessary dietary education starting from childhood. A constant surveillance will be necessary in people carrying E-cadherin mutations, since they are highly prone in developing gastric cancer, also within the inner stomach layers. Above all in the United States, several carriers decided to undergo a gastrectomy, preferring changing their lifestyle than living with the awareness of the development of a possible gastric cancer. This kind of choice is strictly personal, hence a decision cannot be suggested within the clinical management. Here we summarize the key points of gastric cancer prevention analyzing possible strategies referred to the different predisposing factors. We will discuss about the effects of diet, H. pylori infection and E-cadherin mutations and how each of them can be handled.