Reviews and PerspectivesReviews in Basic and Clinical Gastroenterology and HepatologyPathobiology of Helicobacter pylori–Induced Gastric Cancer
Section snippets
Interactions Between Microbial and Human Genetic Ancestries
H pylori strains are highly genetically diverse and thrive as freely recombinogenic populations within their cognate human hosts. One technique that has been used to broadly assess and compare the genetic composition of H pylori strains is multilocus sequence typing. By using this technology, Linz et al4 found that H pylori strains segregated into several major clades that reflected the phylogeographic origins of their corresponding human hosts. These findings, in conjunction with previous data
Virulence Factors
H pylori has evolved the capacity to colonize and persist in one of the harshest environments of the human body, the stomach, which is microbicidal to a large number of species. H pylori use their motility, chemotaxis, urease production, and other mechanisms to adapt to the acidic conditions of the lumen and colonize a narrow protected niche near the surface of epithelial cells. In gastric biopsy specimens and in animal models, most of the bacteria are observed to be free-swimming in the mucus
New Systems for Studying H pylori–Induced Carcinogenesis
Most studies of carcinogenic mechanisms of H pylori have been performed in cancer cell lines, short-term ex vivo primary cell cultures, and infected rodents. However, cell lines that have undergone many passages often contain mutations, and are derived from cancer specimens. In vivo models are expensive and can be time consuming to generate. Isolated ex vivo gastric gland systems are limited by their relatively short life span (eg, 1 week) and a propensity to become heavily contaminated by
Effects on Gastric Stem Cells
Several potential models have been developed to investigate how H pylori infection and its inflammatory response contribute to the dysregulated growth of long-lived cells and eventually cancer. These include infection-induced de-differentiation of terminally differentiated epithelial cells into long-lived, replicating cells; recruitment of mesenchymal stem cells to gastric glands during tissue damage and repair and subsequent transformation of these exogenous stem cells; and/or direct bacterial
H pylori and Iron
Two important clinical observations highlight the relationship between iron and H pylori pathogenesis. One is increasing evidence that H pylori infection is associated with iron-deficiency anemia (IDA), both in sporadic cases of individuals who present with iron-deficiency anemia refractory to iron supplementation118 as well as at a population level related to iron-deficiency anemia of childhood.119 The contribution of H pylori to IDA in childhood likely has a significant health impact in
Salt and H pylori Virulence
A link between high-salt consumption and increased gastric cancer risk has been reported from numerous human studies.133, 134 Gene expression in several bacterial pathogens, including H pylori, can be regulated by salt concentrations.135 Of interest, transcriptional and proteomic studies have shown increased expression of cagA in response to high-salt conditions,136, 137 but only in certain H pylori strains. Based on these findings, Loh et al138 sequenced the cagA promoter in a population of
The Gastrointestinal Microbiota
The role of H pylori in gastric carcinogenesis is undisputed. However, other microbes in the gastric or intestinal niche also could affect transformation of gastric epithelial cells (for review, see Abreu and Peek145). Studies showing the effectiveness of anti–H pylori regimens on gastric cancer incidence raised this possibility by showing that the cancer-lowering effects of antibiotics may be mediated by their effects on non–H pylori residents of the gastrointestinal tract.146 Germ-free
Conclusions
Globally, gastric cancer leads to a high number of cancer-related deaths; increasing our understanding of the risk factors for this disease is of utmost importance in identifying the individuals at greatest risk for developing gastric cancer. Infection with H pylori is extremely common and, in some areas of the world, prevalence rates approach 100%, however, 97%–99% of colonized persons will never develop gastric cancer. The risk of developing gastric cancer is dependent on an opus of
Acknowledgments
Manuel Amieva and Richard Peek were responsible for the analysis and interpretation of previous data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content.
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Conflicts of interest The authors disclose no conflicts.