Helicobacter pyloricauses gastric adenocarcinoma in a minority of infected individuals. What have we learned about bacterial and host-specific factors that lead to malignancy, and what canH. pyloritell us about inflammatory carcinomas that develop beyond the gastric niche? Helicobacter pylori is the dominant species of the human gastric microbiome, and colonization causes a persistent inflammatory response. H. pylori-induced gastritis is the strongest singular risk factor for cancers of the stomach; however, only a small proportion of infected individuals develop malignancy. Carcinogenic risk is modified by strain-specific bacterial components, host responses and/or specific host–microbe interactions. Delineation of bacterial and host mediators that augment gastric cancer risk has profound ramifications for both physicians and biomedical researchers as such findings will not only focus the prevention approaches that target H. pylori-infected human populations at increased risk for stomach cancer but will also provide mechanistic insights into inflammatory carcinomas that develop beyond the gastric niche.

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Helicobacter pylori: gastric cancer and beyond

Infection with strains of Helicobacter pylori that carry the cytotoxin-associated antigen A (cagA) gene is associated with gastric carcinoma. Recent studies have shed light on the mechanism through which the cagA gene product, CagA, elicits pathophysiological actions. CagA is delivered into gastric epithelial cells by the bacterial type IV secretion system, where it deregulates the SHP2 oncoprotein. Intriguingly, CagA is noted for its variation, particularly at the SHP2-binding site, which could affect the potential of different strains of H. pylori to promote gastric carcinogenesis.

Oncogenic mechanisms of the Helicobacter pylori CagA protein

Helicobacter pylori is the main cause of peptic ulceration, distal gastric adenocarcinoma, and gastric lymphoma Only 15% of those colonized develop disease, and pathogenesis depends upon strain virulence, host genetic susceptibility, and environmental cofactors Virulence factors include the cag pathogenicity island, which induces proinflammatory, pro-proliferative epithelial cell signaling; the cytotoxin VacA, which causes epithelial damage; and an adhesin, BabA Host genetic polymorphisms that lead to high-level pro-inflammatory cytokine release in response to infection increase cancer risk Pathogenesis is dependent upon inflammation, a Th-1 acquired immune response and hormonal changes including hypergastrinaemia Antral-predominant inflammation leads to increased acid production from the uninflamed corpus and predisposes to duodenal ulceration; corpus-predominant gastritis leads to hypochlorhydria and predisposes to gastric ulceration and adenocarcinoma Falling prevalence of H pylori in developed countries has led to a falling incidence of associated diseases However, whether there are disadvantages of an H pylori-free stomach, for example increased risk of esosphageal adenocarcinoma, remains unclear

The pathogenesis of helicobacter pylori–induced gastro-duodenal diseases

Helicobacter pylori is a causative agent of gastritis and peptic ulcer. cagA(+) H. pylori strains are more virulent than cagA(-) strains and are associated with gastric carcinoma. The cagA gene product, CagA, is injected by the bacterium into gastric epithelial cells and subsequently undergoes tyrosine phosphorylation. The phosphorylated CagA specifically binds SHP-2 phosphatase, activates the phosphatase activity, and thereby induces morphological transformation of cells. CagA proteins of most Western H. pylori isolates have a 34-amino acid sequence that variably repeats among different strains. Here, we show that the repeat sequence contains a tyrosine phosphorylation site. CagA proteins having more repeats were found to undergo greater tyrosine phosphorylation, to exhibit increased SHP-2 binding, and to induce greater morphological changes. In contrast, predominant CagA proteins specified by H. pylori strains isolated in East Asia, where gastric carcinoma is prevalent, had a distinct tyrosine phosphorylation sequence at the region corresponding to the repeat sequence of Western CagA. This East Asian-specific sequence conferred stronger SHP-2 binding and morphologically transforming activities to Western CagA. Finally, a critical amino acid residue that determines SHP-2 binding activity among different CagA proteins was identified. Our results indicate that the potential of individual CagA to perturb host-cell functions is determined by the degree of SHP-2 binding activity, which depends in turn on the number and sequences of tyrosine phosphorylation sites. The presence of distinctly structured CagA proteins in Western and East Asian H. pylori isolates may underlie the strikingly different incidences of gastric carcinoma in these two geographic areas.

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Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites

Helicobacter pylori plays an essential role in the development of various gastroduodenal diseases; however, only a small proportion of people infected with H. pylori develop these diseases. Some populations that have a high prevalence of H. pylori infection also have a high incidence of gastric cancer (for example, in East Asia), whereas others do not (for example, in Africa and South Asia). Even within East Asia, the incidence of gastric cancer varies (decreasing in the south). H. pylori is a highly heterogeneous bacterium and its virulence varies geographically. Geographic differences in the incidence of gastric cancer can be explained, at least in part, by the presence of different types of H. pylori virulence factor, especially CagA, VacA and OipA. However, it is still unclear why the pathogenicity of H. pylori increased as it migrated from Africa to East Asia during the course of evolution. H. pylori infection is also thought to be involved in the development of duodenal ulcer, which is at the opposite end of the disease spectrum to gastric cancer. This discrepancy can be explained in part by the presence of H. pylori virulence factor DupA. Despite advances in our understanding of the development of H. pylori-related diseases, further work is required to clarify the roles of H. pylori virulence factors.

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Mechanisms of disease: Helicobacter pylori virulence factors

https://www.gastrojournal.org/article/S0016-5085(99)00149-3/pdf

Relationship between the cagA 3' repeat region of Helicobacter pylori, gastric histology, and susceptibility to low pH

Chronic endometritis (CE) is diagnosed via endometrial biopsy and staining for plasma cells. A threshold plasma cell count that identifies CE and predicts pregnancy outcomes has not been established, and the prevalence of plasma cells in the general infertile population is unknown. The purpose of this study was to determine the prevalence of plasma cells in the general infertile population and whether a threshold exists which predicts live birth.Endometrial samples were obtained prospectively from 80 women undergoing IVF, embedded in paraffin, and stained for plasma cells using mouse mono-clonal antibody for CD138. Slides were reviewed at 20× magnification and 10 random images captured. Three reviewers graded each image for plasma cells. Participants underwent single, euploid, and frozen blastocyst transfer.Forty-nine percent of samples had ≥1 plasma cell across 10 HPFs, 11% had ≥5 cells across 10 HPFs, and 4% had ≥10 cells across 10 HPFs. There was no difference in prevalence between those who did and did not achieve live birth. Using thresholds of 1, 5, and 10 plasma cells per 10 HPFs, there were no differences in implantation, clinical pregnancy, clinical pregnancy loss, or live birth rates between patients with and without CE.Endometrial plasma cells are present in half the general infertile population and do not predict implantation, clinical pregnancy, clinical pregnancy loss, or live birth rates at low levels. 

J. K. Kim

Papers

Relationship between the cagA 3' repeat region of Helicobacter pylori, gastric histology, and susceptibility to low pH

The role of endometrial staining for CD138 as a marker of chronic endometritis in predicting live birth