Pathogenesis and risk factors for gastric cancer after Helicobacter pylori eradication

Helicobacter pylori (H. pylori) infection was thought to be the main cause of gastric cancer, and its eradication showed improvement in gastric inflammation and decreased the risk of gastric cancer. Recently, a number of studies reported the occurrence of gastric cancer after successful eradication. Patients infected with H. pylori, even after eradication, have a higher risk for the occurrence of gastric cancer when compared with uninfected patients. Metachronous gastric cancer occurs frequently following the endoscopic removal of early gastric cancer. These data indicate that metachronous cancer leads to the occurrence of gastric cancer even after successful eradication of H. pylori. The pathogenesis of this metachronous cancer remains unclear. Further research is needed to identify biomarkers to predict the development of metachronous gastric cancer and methods for gastric cancer screening. In this article, we review the role of the H. pylori in carcinogenesis and the histological and endoscopic characteristics and risk factors for metachronous gastric cancer after eradication. Additionally, we discuss recent risk predictions and possible approaches for reducing the risk of metachronous gastric cancer after eradication.     

Risk of gastric cancer development after eradication of Helicobacter pylori

Helicobacter pylori (H. pylori) infection is the most important risk factor for gastric cancer (GC) development through the Correa’s gastric carcinogenesis cascade. However, H. pylori eradication alone does not eliminate GC, as pre-neoplastic lesions (atrophic gastritis, intestinal metaplasia and dysplasia) may have already developed in some patients. It is therefore necessary to identify patients at high-risk for gastric cancer after H. pylori eradication to streamline the management plan. If the patients have not undergone endoscopy with histologic assessment, the identification of certain clinical risk factors and non-invasive testing (serum pepsinogen) can predict the risk of atrophic gastritis. For those with suspected atrophic gastritis, further risk stratification by endoscopy with histologic assessment according to validated histologic staging systems would be advisable. Patients with higher stages may require long-term endoscopic surveillance. Apart from secondary prevention to reduce deaths by diagnosing GC at an early stage, identifying medications that could potentially modify the GC risk would be desirable. The potential roles of a number of medications have been suggested by various studies, including proton pump inhibitors (PPIs), aspirin, statins and metformin. However, there are currently no randomized clinical trials to address the impact of these medications on GC risk after H. pylori eradication. In addition, most of these studies failed to adjust for the effect of concurrent medications on GC risk. Recently, large population-based retrospective cohort studies have shown that PPIs were associated with an increased GC risk after H. pylori eradication, while aspirin was associated with a lower risk. The roles of other agents in reducing GC risk after H. pylori eradication remain to be determined.     

Priming the seed: Helicobacter pylori alters epithelial cell invasiveness in early gastric carcinogenesis

Helicobacter pylori (H. pylori) infection is a well-established risk factor for the development of gastric cancer (GC), one of the most common and deadliest neoplasms worldwide. H. pylori infection induces chronic inflammation in the gastric mucosa that, in the absence of treatment, may progress through a series of steps to GC. GC is only one of several clinical outcomes associated with this bacterial infection, which may be at least partially attributed to the high genetic variability of H. pylori. The biological mechanisms underlying how and under what circumstances H. pylori alters normal physiological processes remain enigmatic. A key aspect of carcinogenesis is the acquisition of traits that equip preneoplastic cells with the ability to invade. Accumulating evidence implicates H. pylori in the manipulation of cellular and molecular programs that are crucial for conferring cells with invasive capabilities. We present here an overview of the main findings about the involvement of H. pylori in the acquisition of cell invasive behavior, specifically focusing on the epithelial-to-mesenchymal transition, changes in cell polarity, and deregulation of molecules that control extracellular matrix remodeling.     

Helicobacter pylori infection and gastric carcinoma: Not all the strains and patients are alike

Gastric carcinoma (GC) develops in only 1%-3% of Helicobacter pylori (H. pylori) infected people. The role in GC formation of the bacterial genotypes, gene polymorphisms and host’s factors may therefore be important. The risk of GC is enhanced when individuals are infected by strains expressing the oncoprotein CagA, in particular if CagA has a high number of repeats containing the EPIYA sequence in its C’-terminal variable region or particular amino acid sequences flank the EPIYA motifs. H. pylori infection triggers an inflammatory response characterised by an increased secretion of some chemokines by immunocytes and colonised gastric epithelial cells; these molecules are especially constituted by proteins composing the interleukin-1beta (IL-1β) group and tumour necrosis factor-alpha (TNF-α). Polymorphisms in the promoter regions of genes encoding these molecules, could account for high concentrations of IL-1β and TNF-α in the gastric mucosa, which may cause hypochlorhydria and eventually GC. Inconsistent results have been attained with other haplotypes of inflammatory and anti-inflammatory cytokines. Genomic mechanisms of GC development are mainly based on chromosomal or microsatellite instability (MSI) and deregulation of signalling transduction pathways. H. pylori infection may induce DNA instability and breaks of double-strand DNA in gastric mucocytes. Different H. pylori strains seem to differently increase the risk of cancer development run by the host. Certain H. pylori genotypes (such as the cagA positive) induce high degrees of chronic inflammation and determine an increase of mutagenesis rate, oxidative-stress, mismatch repair mechanisms, down-regulation of base excision and genetic instability, as well as generation of reactive oxygen species that modulate apoptosis; these phenomena may end to trigger or concur to GC development.     

Changes in Pattern of Immunoglobulin Heavy Chain Gene Rearrangement and MIB-1 Staining Before and After Eradication of Helicobacter Pylori in Gastric Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma

Gastric low-grade mucosa-associated lymphoid tissue (MALT) lymphomas are strongly associated with infection by Helicobacter pylori (H. pylori). Antibiotic treatment for H. pylori induces a sustained remission in a significant number of patients. We report here the outcome in 13 patients with gastric low-grade MALT lymphomas or suspected gastric lesions, treated for eradication of H. pylori Patients were followed closely with sequential histological studies, polymerase chain reaction (PCR) amplification of the immunoglobulin heavy chain (IgH) gene and immunohistochemistry for MIB-1. Antibiotic therapy resulted in eradication of H. pylori in all but one case, as assessed histologically. In 12 cases with successful eradication, complete regression was observed histologically in 9 cases (75%) and no regression in 3 (25%). In 7 of 9 (78%) patients who had a complete remission, clonal bands of IgH gene detected on PCR before therapy disappeared after therapy. All 9 patients with complete regression showed a reduced number of MIB-1 positive cells, while 4 cases with no change or disease progression showed no change or increased number of MIB-1 positive cells. There was a strong relationship between density of MIB-1-positive cells and histological score. These results indicate that combination analysis of PCR of IgH and MIB-1 seems to represent a very good current approach for the diagnosis of gastric low-grade MALT lymphoma and to assess the effects of chemotherapy, especially in problematic cases.     

Role of polymorphisms in genes that encode cytokines and Helicobacter pylori virulence factors in gastric carcinogenesis

The Helicobacter pylori (H. pylori) infection is a determinant factor in gastric cancer (GC) development. However, the infection outcomes are variable and depend on both host and bacterial characteristics. Some host cytokines such as interleukin (IL)-1β, IL-1Ra, IL-8, IL-10 and tumor necrosis factor-α play important roles in the host immune system response to the pathogen, in the development of gastric mucosal lesions and in cell malignant transformation. Therefore, these host factors are crucial in neoplastic processes. Certain polymorphisms in genes that encode these cytokines have been associated with an increased risk of GC. On the other hand, various virulence factors found in distinct H. pylori bacterial strains, including cytotoxin-associated antigen A, vacuolating cytotoxin, duodenal ulcer promoting gene A protein, outer inflammatory protein and blood group antigen binding adhesin, have been associated with the pathogenesis of different gastric diseases. The virulent factors mentioned above allow the successful infection by the bacterium and play crucial roles in gastric mucosa lesions, including malignant transformation. Moreover, the role of host polymorphisms and bacterial virulence factors in gastric carcinogenesis seems to vary among different countries and populations. The identification of host and bacterium factors that are associated with an increased risk of GC development may be useful in determining the prognosis of infection in patients, what could help in clinical decision-making and in providing of an optimized clinical approach.     

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.     

Radiotherapy for gastric mucosa-associated lymphoid tissue lymphoma

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a rare disease which is often associated with Helicobacter pylori (H. pylori) infection. First-line treatment of stage IE and IIE localized gastric MALT lymphoma is based on the eradication of H. pylori. The presence of H. pylori resistance factors such as translocation t (11;18), peri-gastric lymph node involvement and the degree of tumor infiltration of the gastric wall; or lack of response to antibiotic therapy are two main indications to treat with definitive radiotherapy (RT). RT is an effective treatment in localized gastric MALT lymphoma. A moderate dose of 30 Gy allows a high cure rate while being well tolerated. After treatment, regular gastric endoscopic follow-up is necessary to detect a potential occurrence of gastric adenocarcinoma.     

Effects of Helicobacter pylori infection in gastrointestinal tract malignant diseases: From the oral cavity to rectum

Helicobacter pylori (H. pylori) has infected approximately fifty percent of humans for a long period of time. However, improvements in the public health environment have led to a decreased chance of H. pylori infection. However, a high infection rate is noted in populations with a high incidence rate of gastric cancer (GC). The worldwide fraction of GC attributable to H. pylori is greater than 85%, and a high H. pylori prevalence is noted in gastric mucosa-associated lymphoid tissue lymphoma patients. These results indicate that the majority of GC cases can be prevented if H. pylori infection is eliminated. Because H. pylori exhibits oral-oral or fecal-oral transmission, the relationship between this microorganism and other digestive tract malignant diseases has also attracted attention. This review article provides an overview of H. pylori and the condition of the whole gastrointestinal tract environment to further understand the correlation between the pathogen and the host, thus allowing improved realization of disease presentation.     

Helicobacter pylori infection and other bacteria in pancreatic cancer and autoimmune pancreatitis

Helicobacter pylori (H. pylori) is an infectious agent influencing as much as 50% of the world’s population. It is the causative agent for several diseases, most especially gastric and duodenal peptic ulcer, gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma of the stomach. A number of other, extragastric manifestations also are associated with H. pylori infection. These include neurological disorders, such as Alzheimer’s disease, demyelinating multiple sclerosis and Parkinson’s disease. There is also evidence for a relationship between H. pylori infection and such dermatological diseases as psoriasis and rosacea as well as a connection with infection and open-angle glaucoma. Generally little is known about the relationship between H. pylori infection and diseases of the pancreas. Most evidence about H. pylori and its potential role in the development of pancreatic diseases concerns pancreatic adenocarcinoma and autoimmune forms of chronic pancreatitis. There is data (albeit not fully consistent) indicating modestly increased pancreatic cancer risk in H. pylori-positive patients. The pathogenetic mechanism of this increase is not yet fully elucidated, but several theories have been proposed. Reduction of antral D-cells in H. pylori-positive patients causes a suppression of somatostatin secretion that, in turn, stimulates increased secretin secretion. That stimulates pancreatic growth and thus increases the risk of carcinogenesis. Alternatively, H. pylori, as a part of microbiome dysbiosis and the so-called oncobiome, is proven to be associated with pancreatic adenocarcinoma development via the promotion of cellular proliferation. The role of H. pylori in the inflammation characteristic of autoimmune pancreatitis seems to be explained by a mechanism of molecular mimicry among several proteins (mostly enzymes) of H. pylori and pancreatic tissue. Patients with autoimmune pancreatitis often show positivity for antibodies against H. pylori proteins. H. pylori, as a part of microbiome dysbiosis, also is viewed as a potential trigger of autoimmune inflammation of the pancreas. It is precisely these relationships (and associated equivocal conclusions) that constitute a center of attention among pancreatologists, immunologists and pathologists. In order to obtain clear and valid results, more studies on sufficiently large cohorts of patients are needed. The topic is itself sufficiently significant to draw the interest of clinicians and inspire further systematic research. Next-generation sequencing could play an important role in investigating the microbiome as a potential diagnostic and prognostic biomarker for pancreatic cancer.     

Mucosa-associated lymhpoid tissue (MALT) lymphoma of the jejunum and Helicobacter pylori--chance association?

Helicobacter pylori have been causally linked to primary gastric B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type. Antibiotic therapy to eradicate H. pylori has been shown to induce remission of such lymphoma. We report a case of primary B-cell MALT lymphoma of the jejunum associated with H. pylori. The literature of intestinal MALT lymphoma is reviewed.     

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.     

Low-grade MALT lymphoma of the stomach: a review of treatment options

Purpose: Low-grade mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach (MLS) is often associated with the presence of Helicobacter pylori (H. pylori) bacteria. Eradication of the infection with antibiotic therapy may result in regression of the lymphoma. But when antibiotic treatment fails to reverse the malignant process or if H. pylori is absent, other treatment options should be considered. Because MLS is often confined to the stomach and regional lymph nodes, it is potentially curable with local therapy. Endoscopy and improved imaging, with endoscopic ultrasound (EUS) and computerized tomography (CT), have reduced the prior dependence on surgery for diagnosis and staging of gastric lymphomas.

Methods and Results: This review details the advances in the diagnosis, classification, and imaging of MLS. We also describe the experience that supports the use of radiation therapy as the preferred treatment of MLS in patients who have not responded to antibiotic therapy or have not had evidence for H. pylori infection.

Conclusions: Radiation therapy for MLS is not only effective and safe, but offers the significant advantage of low morbidity and gastric function preservation.     

Influence of Helicobacter pylori oncoprotein CagA in gastric cancer: A critical-reflective analysis

Gastric cancer is the fifth most common malignancy and third leading cancer-related cause of death worldwide. Helicobacter pylori is a Gram-negative bacterium that inhabits the gastric environment of 60.3% of the world’s population and represents the main risk factor for the onset of gastric neoplasms. CagA is the most important virulence factor in H. pylori, and is a translocated oncoprotein that induces morphofunctional modifications in gastric epithelial cells and a chronic inflammatory response that increases the risk of developing precancerous lesions. Upon translocation and tyrosine phosphorylation, CagA moves to the cell membrane and acts as a pathological scaffold protein that simultaneously interacts with multiple intracellular signaling pathways, thereby disrupting cell proliferation, differentiation and apoptosis. All these alterations in cell biology increase the risk of damaged cells acquiring pro-oncogenic genetic changes. In this sense, once gastric cancer sets in, its perpetuation is independent of the presence of the oncoprotein, characterizing a “hit-and-run” carcinogenic mechanism. Therefore, this review aims to describe H. pylori- and CagA-related oncogenic mechanisms, to update readers and discuss the novelties and perspectives in this field.     

Association study of a functional Toll-like receptor 4 polymorphism with susceptibility to gastric mucosa-associated lymphoid tissue lymphoma

Toll-like receptor 4, as part of innate immune response, is the main receptor for lipopolysaccharide on marginal zone B cells. The rare allele of TLR4 Asp299Gly attenuates receptor signaling and diminishes the inflammatory response. We genotyped 87 patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma, 594 Helicobacter pylori positive controls and 358 healthy blood donors to investigate an association of TLR4 Asp299Gly in the development of gastric MALT lymphoma. Heterozygote genotype was significantly less frequent in patients with gastric MALT lymphoma compared to H. pylori-infected controls (4.6% vs. 11.6%, Fischer's exact P = 0.019, odds ratio = 0.37, 95% confidence interval 0.13 - 1.03). Because 10% of caucasians are carriers of the rare allele G TLR4 Asp299Gly appears to be only one factor in the genetic susceptibility to gastric lymphoma. Further studies in larger samples are needed to confirm our findings and fully elucidate the role of TLR4 and its genetic variants in the pathophysiology of H. pylori infection and gastric lymphoma.     

Evaluation of polygenic risk score for risk prediction of gastric cancer

Genetic variations are associated with individual susceptibility to gastric cancer.Recently, polygenic risk score(PRS) models have been established based on genetic variants to predict the risk of gastric cancer. To assess the accuracy of current PRS models in the risk prediction, a systematic review was conducted. A total of eight eligible studies consisted of 544842 participants were included for evaluation of the performance of PRS models. The overall accuracy was moderate with Area under the...     

Sporadic fundic gland polyps with dysplasia or carcinoma: Clinical and endoscopic characteristics

Fundic gland polyps (FGPs) are the most common gastric polyps and have been regarded as benign lesions with little malignant potential, except in the setting of familial adenomatous polyposis. However, in recent years, the prevalence of FGPs has been increasing along with the widespread and frequent use of proton pump inhibitors (PPIs). To date, several cases of FGPs with dysplasia or carcinoma (FGPD/CAs) have been reported. In this review, we evaluated the clinical and endoscopic characteristics of sporadic FGPD/CAs. Majority of the patients with sporadic FGPD/CAs were middle-aged women receiving PPI therapy and without Helicobacter pylori (H. pylori) infection. Majority of the sporadic FGPD/ CAs occurred in the body of the stomach and were sessile and small with a mean size of 5.4 mm. The sporadic FGPs with carcinoma showed redness, irregular surface structure, depression, or erosion during white light observation and irregular microvessels on the lesion surface during magnifying narrow-band imaging. In addition, sporadic FGPs, even with dysplasia, are likely to progress to cancer slowly. Therefore, frequent endoscopy is not required for patients with sporadic FGPs. However, histopathological evaluation is necessary if endoscopic findings different from ordinary FGPs are observed, regardless of their size. In the future, the prevalence of FGPs is expected to further increase along with the widespread and frequent use of PPIs and decreasing infection rate of H. pylori. Currently, it is unclear whether FGPD/CAs will also increase in the same way as FGPs. However, the trends of these lesions warrant further attention in the future.     

ADAM23, a possible tumor suppressor gene, is frequently silenced in gastric cancers by homozygous deletion or aberrant promoter hypermethylation

Array-based comparative genomic hybridization (CGH-array) has a powerful potential for high-throughput identification of genetic aberrations in cell genomes. We identified a homozygous loss of ADAM23 (2q33.3) in the course of a program to screen a panel of gastric cancer (GC) cell lines (1/32, 3.1%) for genomic copy-number aberrations using our custom-made CGH-array. Infrequent homozygous deletion of ADAM23 was also seen in primary gastric tumors (1/39, 2.6%). ADAM23 mRNA was expressed in normal stomach tissue, but not in the majority of GC cell lines without homozygous deletion of this gene. Expression of ADAM23 mRNA was restored to gene-silenced GC cells after treatment with 5-aza 2'-deoxycytidine. The methylation status of the ADAM23 CpG island, which showed promoter activity, correlated inversely with its expression. Methylation of this CpG island was observed both in GC cell lines and in primary GC tissues; in primary tumors with a hypermethylated CpG island, expression of ADAM23 was lower than in adjacent noncancerous tissues. Moreover, restoration of ADAM23 in GC cells reduced their numbers in colony-formation assays. These results suggest that genetic or epigenetic silencing by hypermethylation of the ADAM23 CpG-rich promoter region leads to loss of ADAM23 function, which may be a factor in gastric carcinogenesis.     

Gastric cancer: An epigenetic view

Gastric cancer (GC) poses a serious threat worldwide with unfavorable prognosis mainly due to late diagnosis and limited therapies. Therefore, precise molecular classification and search for potential targets are required for diagnosis and treatment, as GC is complicated and heterogeneous in nature. Accumulating evidence indicates that epigenetics plays a vital role in gastric carcinogenesis and progression, including histone modifications, DNA methylation and non-coding RNAs. Epigenetic biomarkers and drugs are currently under intensive evaluations to ensure efficient clinical utility in GC. In this review, key epigenetic alterations and related functions and mechanisms are summarized in GC. We focus on integration of existing epigenetic findings in GC for the bench-to-bedside translation of some pivotal epigenetic alterations into clinical practice and also describe the vacant field waiting for investigation.     

Genomic loss and epigenetic silencing of very-low-density lipoprotein receptor involved in gastric carcinogenesis

Homozygous loss in the genomic sequence, a mechanism for inactivating tumor-suppressor genes (TSGs) in cancer, has been used as a tag for the identification of novel TSGs, and array-based comparative genomic hybridization (array-CGH) has a great potential for high-throughput identification of this change. We identified a homozygous loss of the very-low-density lipoprotein receptor (VLDLR) gene (9p24.2) from genome-wide screening for copy-number alterations in 32 gastric cancer (GC) cell lines using array-CGH. Although previous reports demonstrated mRNA or protein expression of VLDLR in various cancers including GC, the association between genomic losses or epigenetic silencing of this gene and carcinogenesis has never been reported before. Homozygous deletion of VLDLR was also seen in primary GCs, albeit infrequently, and about half of GC cell lines showed lost or reduced VLDLR expression. The VLDLR expression was restored in gene-silenced GC cells after treatment with 5-aza 2'-deoxycytidine. According to methylation analyses, hypermethylation of the VLDLR promoter region, which all of GC lines without its expression showed, occurred in some primary GCs. Restoration of VLDLR type I expression in GC cells reduced colony formation. These results suggest that not only the expression of VLDLR but also genetic or epigenetic silencing of this gene may contribute to tumor formation and be involved in gastric carcinogenesis.