Gastroenterology

Gastroenterology

Volume 150, Issue 1, January 2016, Pages 64-78
Gastroenterology

Reviews and Perspectives
Reviews in Basic and Clinical Gastroenterology and Hepatology
Pathobiology of Helicobacter pylori–Induced Gastric Cancer

https://doi.org/10.1053/j.gastro.2015.09.004Get rights and content

Colonization of the human stomach by Helicobacter pylori and its role in causing gastric cancer is one of the richest examples of a complex relationship among human cells, microbes, and their environment. It is also a puzzle of enormous medical importance given the incidence and lethality of gastric cancer worldwide. We review recent findings that have changed how we view these relationships and affected the direction of gastric cancer research. For example, recent data have indicated that subtle mismatches between host and microbe genetic traits greatly affect the risk of gastric cancer. The ability of H pylori and its oncoprotein CagA to reprogram epithelial cells and activate properties of stemness show the sophisticated relationship between H pylori and progenitor cells in the gastric mucosa. The observation that cell-associated H pylori can colonize the gastric glands and directly affect precursor and stem cells supports these observations. The ability to mimic these interactions in human gastric organoid cultures as well as animal models will allow investigators to more fully unravel the extent of H pylori control on the renewing gastric epithelium. Finally, our realization that external environmental factors, such as dietary components and essential micronutrients, as well as the gastrointestinal microbiota, can change the balance between H pylori’s activity as a commensal or a pathogen has provided direction to studies aimed at defining the full carcinogenic potential of this organism.

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.

References (150)

  • N. Barker et al.

    Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro

    Cell Stem Cell

    (2010)
  • L.E. Wroblewski et al.

    Helicobacter pylori dysregulation of gastric epithelial tight junctions by urease-mediated myosin II activation

    Gastroenterology

    (2009)
  • T.A. Nagy et al.

    β-Catenin and p120 mediate PPARdelta-dependent proliferation induced by Helicobacter pylori in human and rodent epithelia

    Gastroenterology

    (2011)
  • Q. Li et al.

    Diphtheria toxin-mediated ablation of parietal cells in the stomach of transgenic mice

    J Biol Chem

    (1996)
  • J.D. Oh et al.

    Interactions between gastric epithelial stem cells and Helicobacter pylori in the setting of chronic atrophic gastritis

    Curr Opin Microbiol

    (2006)
  • B.K. Koo et al.

    Stem cells marked by the R-spondin receptor LGR5

    Gastroenterology

    (2014)
  • D.M. Hardbower et al.

    At the bench: Helicobacter pylori, dysregulated host responses, DNA damage, and gastric cancer

    J Leukoc Biol

    (2014)
  • D.M. Parkin et al.

    Global cancer statistics, 2002

    CA Cancer J Clin

    (2005)
  • D.B. Polk et al.

    Helicobacter pylori: gastric cancer and beyond

    Nat Rev Cancer

    (2010)
  • B. Linz et al.

    An African origin for the intimate association between humans and Helicobacter pylori

    Nature

    (2007)
  • Y. Moodley et al.

    Age of the association between Helicobacter pylori and man

    PLoS Pathog

    (2012)
  • N. Kodaman et al.

    Human and Helicobacter pylori coevolution shapes the risk of gastric disease

    Proc Natl Acad Sci U S A

    (2014)
  • N. Kodaman et al.

    Disrupted human-pathogen co-evolution: a model for disease

    Front Genet

    (2014)
  • C. Holcombe

    Helicobacter pylori: the African enigma

    Gut

    (1992)
  • P. Correa et al.

    Gastric cancer in Colombia. III. Natural history of precursor lesions

    J Natl Cancer Inst

    (1976)
  • T. de Sablet et al.

    Phylogeographic origin of Helicobacter pylori is a determinant of gastric cancer risk

    Gut

    (2011)
  • H. Song et al.

    Incidence of gastric cancer among patients with gastric precancerous lesions: observational cohort study in a low risk Western population

    BMJ

    (2015)
  • C. Figueiredo et al.

    Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma

    J Natl Cancer Inst

    (2002)
  • S. Schreiber et al.

    The spatial orientation of Helicobacter pylori in the gastric mucus

    Proc Natl Acad Sci U S A

    (2004)
  • S. Schreiber et al.

    Rapid loss of motility of Helicobacter pylori in the gastric lumen in vivo

    Infect Immun

    (2005)
  • E.D. Segal et al.

    Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori

    Proc Natl Acad Sci U S A

    (1999)
  • S. Backert et al.

    Translocation of the Helicobacter pylori CagA protein in gastric epithelial cells by a type IV secretion apparatus

    Cell Microbiol

    (2000)
  • S. Odenbreit et al.

    Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion

    Science

    (2000)
  • M. Stein et al.

    Tyrosine phosphorylation of the Helicobacter pylori CagA antigen after cag-driven host cell translocation

    Proc Natl Acad Sci U S A

    (2000)
  • J. Viala et al.

    Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island

    Nat Immunol

    (2004)
  • G. Suarez et al.

    Modification of Helicobacter pylori peptidoglycan enhances NOD1 activation and promotes cancer of the stomach

    Cancer Res

    (2015)
  • M.J. Blaser et al.

    Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach

    Cancer Res

    (1995)
  • S. Censini et al.

    cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors

    Proc Natl Acad Sci U S A

    (1996)
  • D. Mueller et al.

    c-Src and c-Abl kinases control hierarchic phosphorylation and function of the CagA effector protein in Western and East Asian Helicobacter pylori strains

    J Clin Invest

    (2012)
  • T.A. Nagy et al.

    Helicobacter pylori regulates cellular migration and apoptosis by activation of phosphatidylinositol 3-kinase signaling

    J Infect Dis

    (2009)
  • S. Keates et al.

    Differential activation of mitogen-activated protein kinases in AGS gastric epithelial cells by cag+ and cag- Helicobacter pylori

    J Immunol

    (1999)
  • H. Higashi et al.

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

    Proc Natl Acad Sci U S A

    (2002)
  • A.T. Franco et al.

    Activation of B-catenin by carcinogenic Helicobacter pylori

    Proc Natl Acad Sci U S A

    (2005)
  • N. Murata-Kamiya et al.

    Helicobacter pylori CagA interacts with E-cadherin and deregulates the beta-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells

    Oncogene

    (2007)
  • J.T. Neal et al.

    H pylori virulence factor CagA increases intestinal cell proliferation by Wnt pathway activation in a transgenic zebrafish model

    Dis Models Mech

    (2013)
  • L. Buti et al.

    Helicobacter pylori cytotoxin-associated gene A (CagA) subverts the apoptosis-stimulating protein of p53 (ASPP2) tumor suppressor pathway of the host

    Proc Natl Acad Sci U S A

    (2011)
  • J. Wei et al.

    Bacterial CagA protein induces degradation of p53 protein in a p14ARF-dependent manner

    Gut

    (2015)
  • Y.H. Tsang et al.

    Helicobacter pylori CagA targets gastric tumor suppressor RUNX3 for proteasome-mediated degradation

    Oncogene

    (2010)
  • I. Saadat et al.

    Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity

    Nature

    (2007)
  • Z. Zeaiter et al.

    Analysis of detergent-resistant membranes of Helicobacter pylori infected gastric adenocarcinoma cells reveals a role for MARK2/Par1b in CagA-mediated disruption of cellular polarity

    Cell Microbiol

    (2008)
  • Cited by (0)

    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by National Institutes of Health grants CA-116087, DK-58404, DK-58587, and CA-77955.

    View full text