Helicobacter pylori and Gastric Cancer

H. pylori Infection, Gastric Cancer and Related Pathologies
Dig Dis 2014;32:249–264
DOI: 10.1159/000357858
Helicobacter pylori and Gastric Cancer
Jan Bornschein a, b Peter Malfertheiner a
a
Department of Gastroenterology, Hepatology and Infectious Diseases, Otto von Guericke University of
Magdeburg, Magdeburg, Germany; b MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre,
Cambridge, UK
Abstract
Infection with Helicobacter pylori is established as the major
risk factor for gastric cancer development. Damage of the
mucosal barrier due to H. pylori-induced inflammation enhances the carcinogenic effect of other risk factors such as
salt intake or tobacco smoking. The genetic disposition of
both the bacterial strain and the host can increase the potential towards gastric cancer formation. Genetic variance of
the bacterial proteins CagA and VacA is associated with a
higher gastric cancer risk, as are polymorphisms and epigenetic changes in host gene coding for interleukins (IL1β, IL8),
transcription factors (CDX2, RUNX3) and DNA repair enzymes. Application of high-throughput assays for genomewide assessment of either genetic structural variance or
gene expression patterns may lead to a better understanding of the pathobiological background of these processes,
including the underlying signaling pathways. Understanding of the stepwise alterations that take place in the transition from chronic atrophic gastritis, via metaplastic changes,
to invasive neoplasia is vital to define the ‘point of no return’
before which eradication of H. pylori has the potential to prevent gastric cancer. Currently, eradication as preventive
© 2014 S. Karger AG, Basel
0257–2753/14/0323–0249$39.50/0
E-Mail karger@karger.com
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strategy is only recommended for high-incidence regions in
Asia; large population studies with an adequate follow-up
are required to demonstrate the effectiveness of such an approach in Western populations.
© 2014 S. Karger AG, Basel
Helicobacter pylori – Epidemiological Background
In 1994, the WHO classified Helicobacter pylori as
class I carcinogen based on epidemiological evidence for
its role in the pathogenesis of gastric cancer, which has
been reinforced in 2010 [1, 2]. In 1998, H. pylori was first
shown to act as a complete carcinogen, inducing gastric
adenocarcinomas without the influence of any cocarcinogens, in a Mongolian gerbil animal model [3, 4]. However, supplementation of the animals with nitrosamines
led to higher rates of cancer incidence and a more rapid
carcinogenesis suggesting a multifactorial process [5, 6].
The attributable risk of H. pylori infection for gastric carcinogenesis in humans has long been debated.
In earlier studies based on H. pylori serology, the odds
ratio (OR) for gastric cancer development ranged between 2 and 6 [7]. In a 7.8-years observational study of
1,526 patients who underwent gastroscopy for dyspepsia, gastric adenocarcinoma developed only in 36 patients (2.9%) infected with H. pylori, and not in noninProf. Dr. med. Dr. h. c. mult. Peter Malfertheiner
Department of Gastroenterology, Hepatology and Infectious Diseases
Otto von Guericke University of Magdeburg
Leipziger Strasse 44, DE–39120 Magdeburg (Germany)
E-Mail peter.malfertheiner @ med.ovgu.de
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Key Words
Gastric cancer · Gastritis · Helicobacter pylori ·
Interleukin-1β · Intestinal metaplasia · CagA protein
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H. pylori and Environmental Risk Factors
In 1997, a combined analysis of 16 case-control studies
demonstrated an association between salt intake and the
risk of gastric cancer [19–21]. Animal studies had previously indicated that ingested salt can affect the gastric
mucosal barrier leading to inflammation, diffuse erosions
and epithelial degeneration [22–24]. There is a lively debate which carcinogen is the leading agent if both H. pylori infection and high-salt diet are present. In a mouse
model, high salt intake led to severe gastritis and a higher
degree of epithelial proliferation compared to the low-salt
group, but H. pylori-induced intraepithelial neoplasia developed in both diet groups at a similar rate [25]. In Mongolian gerbils, the incidence of gastric cancer increased
with rising concentration of salt in the animals’ diet [26].
This was independent of H. pylori infection status, but
only in the presence of N-methyl-N-nitrosurea as additional strong carcinogen. Salt intake can lead to an upregulation of the expression of iNOS (inducible nitric oxide synthetase) and COX2 (cyclooxygenase 2) synergistically to the induction by H. pylori [27]. Salt furthermore
increases the colonization of the gastric mucosa with H.
pylori and enhances CagA-related inflammatory effects
and their consequences including the proinflammatory
cytokine milieu and later mucosal changes like atrophic
gastritis [28, 29]. Exposition to high salt concentrations
leads to an increased expression of CagA and increasing
levels of interleukin-8 (IL8) as epithelial response [30].
This effect is confirmed for H. pylori strains that carry two
copies of a specific motif of their cagA promotor region
(TAATGA) [31].
Human studies demonstrated a significant salt effect
only in H. pylori-positive patients in whom the gastric
mucosa was already ‘pre-damaged’ by H. pylori-induced
chronic active inflammation [21, 32]; a prospective study
suggested that high salt intake had the strongest effect on
gastric carcinogenesis in patients with both H. pylori infection and glandular atrophy in the stomach [32]. However, a case control study on 422 gastric cancer patients
and 649 controls demonstrated a 2-fold increase in gastric
cancer in patients with high salt intake, which was independent of other risk factors like H. pylori infection of
smoking [33]. Despite the increasing knowledge, the exact interplay between salt-related damage of the gastric
mucosa and H. pylori-driven inflammation needs further
elucidation.
H. pylori infection reduces the bioavailability of vitamin C, leading subsequently to decreased concentrations
in plasma and gastric juice [34], whereas the luminal conBornschein /Malfertheiner
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fected individuals [8]. A meta-analysis from Asia of 19
studies with approximately 2,500 gastric cancer patients
and almost 4,000 matched controls showed an OR of
1.92 (95% confidence interval, CI: 1.32–2.78) for the development of non-cardia gastric cancer in H. pylori-positive patients [9], which was in concordance with a previous meta-analysis [10]. In 2003, the Helicobacter and
Cancer Collaborative Group combined data from all
available case control studies nested with prospective cohorts. Overall, 1,228 patients were included, and H. pylori infection was shown to be associated with non-cardia gastric cancer (OR 3.0, 95% CI: 2.3–3.8). The association was strengthened when H. pylori serology was
performed ≥10 years before the cancer diagnosis (OR
5.9; 95% CI: 3.4–10.3) [11]. The explanation for the increased OR is that if sera were taken before disease manifestation, H. pylori colonization would likely disappear
in the presence of atrophic gastritis and intestinal metaplasia (IM), and thus gastric cancer patients may present
with a loss of anti-H. pylori antibodies at the time of disease manifestation. In fact, patients with early gastric
cancer have a much higher prevalence of H. pylori antibodies when compared to those with advanced gastric
cancer, resulting in a different attributable risk [9]. The
time of serum sampling is crucial as was further proven
by another study in which development of gastric cancer
in the case of H. pylori infection was significantly higher
if serum samples were taken within 90 days after tumor
gastrectomy [12].
The attributable risk totally changed with the study of
Ekström et al. [13] who reported an increase of the H.
pylori-attributable OR for non-cardia cancer from 2.2 to
21.0 if the expression of the cytotoxic antigen A (CagA),
a bacterial virulence factor, was coevaluated with anti-H.
pylori serology by immunoblot analysis. In this analysis,
71–91% of gastric cancer was attributable to H. pylori infection. Antibodies to CagA persist longer in the serum
than anti-H. pylori IgG so that evaluation of certain bacterial virulence factors may provide more precise results
for the H. pylori-attributable risk for gastric carcinogenesis [14].
While early studies claim that H. pylori infection is
only related to distal or ‘non-cardia’ gastric cancer, this is
no longer true since there is clear evidence now for the
pathogenetic relevance also in proximal gastric cancer or
adenocarcinomas at the esophagogastric junction, if
proper allocation of the tumor and assessment of the relevant risk factor are performed [15–17]. The risk for gastric carcinogenesis by H. pylori infection is similar for intestinal- and diffuse-type gastric cancers [15, 18].
H. pylori Virulence Factors
Bacterial virulence factors influence the malignant potential of H. pylori [48]. Best investigated is the cag pathogenicity island (cagPAI) type IV secretion system necesH. pylori and Gastric Cancer
sary for translocation of pathogenetic factors of H. pylori
(e.g. CagA) into the epithelial cell [49, 50], which can induce a more severe inflammatory response, also increasing the risk for gastric carcinogenesis [51–53]. Injected
CagA is rapidly phosphorylated by host Src kinases and
has the potential to change intracellular signal transduction and to disrupt epithelial cell junctions [54, 55]. CagA
leads to the activation of the Ras-mitogen-activated protein kinase pathway, involving the Ras-dependent kinases ERK1 and ERK2 with further transactivation of hostrelated pathways [56–58]. CagA-dependent activation of
the Ras-ERK cascade increases also IL8 release and NFκB
activation inducing the invasion of neutrophil granulocytes into the gastric mucosa [59]. NFκB-related carcinogenesis is enhanced by H. pylori-associated release of tumor necrosis factor-α-inducing protein (Tipα) enhancing the expression of TNFα with further involvement of
IL8- and COX2-dependent pathways [60, 61]. Interaction
of CagA with the E-cadherin/β-catenin system can lead
to a direct transactivation of CDX1 and by this to metaplastic changes in the mucosa [62]. CagA is further
thought to contribute to epithelial-mesenchymal transition, a hallmark of epithelial-derived carcinogenesis [63,
64].
Once intracellular, CagA is phosphorylated at certain
glutamate-isoleucine-tyrosine-alanine (EPIYA) motifs.
Four distinct EPIYA motifs are described (EPIYA-A, -B,
-C, -D) [65, 66] whose prevalence varies by geographical
region. They further influence the CagA-induced immune response as well as the related cancer risk. The OR
for gastric cancer is about 7.3 in the case of one EPIYA-C
segment, and can be up to 51 in the case of two or more
segments [67, 68]. Relatives of patients with gastric cancer have been shown to carry H. pylori strains with a
higher frequency of EPIYA-C segments [69]. Recently,
genetic variations in further cagPAI-related genes have
been demonstrated to be associated with gastric cancer
[70].
A similar diversity has been identified for the vacuolating cytotoxin A (VacA) showing variations in its gene
structure which can be divided into a signaling (s), a middle (m), and an intermediate (i) region [48]. After the first
identification of s1/m1 strains showing a higher attributable risk for gastric cancer development, also i1 strains
have been demonstrated to be associated with not only
dysplastic but also malignant invasive tissue formation
[67, 69, 71]. VacA has an inhibitory effect on GSK3β (glycogen synthase kinase 3-β)-regulated signaling pathways
by phosphorylation through an Akt/PI3K (phosphatidylinositol-3-kinase)-mediated pathway, which leads to
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centration of reactive oxygen species in the stomach is
increased [35]. Supplementation of vitamin C after H. pylori eradication can lead to a regression of premalignant
lesions [36]. However, the EPIC (European Prospective
Investigation into Cancer and Nutrition) study of more
than 500,000 participants in 10 countries could not confirm an association of plasma vitamin C levels with gastric
cancer development when confounding factors like body
mass index, total energy intake, smoking, and H. pylori
status were considered [37].
More than 40 mostly retrospective epidemiological
studies have not confirmed the association between
chronic alcohol consumption and gastric adenocarcinomas including cardia cancer [38–40]. However, a recent
publication from the EPIC cohort reported an increased
risk for gastric carcinogenesis for heavy alcohol consumption (>60 g per day) compared to very low intake
(0.1–4.9 g per day) with a hazard ratio (HR) of 1.65 (95%
CI: 1.06–2.58) [41].
Results of a systematic review analyzing the relation
between cigarette smoking and gastric cancer including
42 cohort, case-cohort and case-control studies demonstrated that smoking is significantly associated with an
elevated relative risk (RR) for both gastric cardia (RR =
1.87; 95% CI: 1.31–2.67) and non-cardia cancers (RR =
1.60; 95% CI: 1.41–1.80) [42]. This agrees with a previous
meta-analysis [43] and the EPIC study which estimated
that 17.6% (95% CI: 10.5–29.5%) of gastric cancers are
related to smoking [42]. In a review analyzing the interaction of alimentary carcinogenic agents with H. pylori infection, the OR for the combined presence of both H. pylori and cocarcinogens was highest in all studies (2.3–
19.0), although no trial revealed an additive effect, and the
statistical analysis for risk factor interaction was negative
[44]. In comparison, the increased risk for gastric carcinogenesis in persons with a high intake of meat (total
meat, processed meat and red meat: OR 1.93–5.32) was
demonstrated only in H. pylori-positive subjects [45].
The postulated protective effect of fruits and vegetables, with high plasma levels of vitamin C, vitamin E and
retinol as surrogate indicators, was only confirmed for H.
pylori-positive individuals, although this interaction
could not be statistically confirmed [37, 46, 47].
Host-Related Factors
Epigenetic Changes
H. pylori-driven inflammation can lead to methylation
of CpG islands in gene promoters through the release of
reactive oxygen species and nitric oxide, and by activation
of the DNA methyltransferase [82, 83]. These epigenetic
changes correlate with the degree of gastric inflammation
and increase with the development of premalignant
changes of the gastric mucosa and finally gastric neoplasia
[84–86]. Eradication of the infection can decrease general
methylation levels [87], but this effect is not consistent for
all affected genes [88]. H. pylori-related methylation alters
not only the function of common oncogenes or tumor
suppressor genes but also transcription factors like forkhead box proteins (FOX) and the Runt-related transcription factor 3 (RUNX3), which show an association of the
degree of methylation with distinct stages of gastric cancer
progression and local invasive behavior [89, 90]. It seems
that the respective methylation profiles are different for
intestinal- and diffuse-type gastric cancer [91].
Global demethylation of the tumor cell genome in gastric cancer occurs in parallel to abnormal hypermethylation of tumor suppressor genes [92]. The global methylation patterns which can also be assessed by a serumbased test can define different gastric cancer subtypes
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[93] and show a potential to be used as a marker to detect
metastasis and therefore may reflect the malignant potential of gastric cancer [86, 94].
Gene Polymorphisms of Immune Response Genes
Hereditary gastric cancer is generally of the diffuse
type and characterized by mutation in the CDH1 gene
that is coding for E-cadherin [95]. However, sporadic genetic alterations, mainly single nucleotide polymorphisms (SNPs) of factors that modulate and mediate the
inflammatory response to H. pylori infection, have been
reported to have a broad influence on gastric cancer susceptibility [96, 97]. Among these are cytokine genes involved in the adaptive immune system [98–100] and pattern recognition factors initiating the innate immune system [101, 102]. Furthermore, variation of genes encoding
for proteases [103], xenobiotic metabolism enzymes
[104], cell cycle regulators [105, 106], mucins [107], HLA
molecules [108], transcription factors [109], DNA repair
enzymes [105, 110, 111], and micro-RNAs [112] has been
reported to bear an increased risk for gastric cancer. Besides a ‘single gene’ approach, also pathway-related pattern searches can be performed to allow a broader assessment of the pathobiological background [113]. The identified SNPs might also have an effect on gastric cancer risk
in relatives of the index patients [114].
IL1β, the most powerful proinflammatory cytokine
produced in response to H. pylori infection, is known to
also act as a strong acid inhibitor [115]. It has been postulated that carriers of specific SNPs in the IL1β gene or
the gene of the IL1 receptor antagonist (IL1RN) have an
up to 4-fold increased risk for developing gastric cancer
[116]. Numerous studies in various ethnic groups have
been published since the first report revealing conflicting
results [117–120].
A meta-analysis demonstrated a decreasing association
of these polymorphisms with gastric cancer risk for the accumulative data up to 2006 [121]. The OR for gastric cancer
in the case of present IL1β gene mutation varies from 0.82
to 1.99 depending on the geographic region, the histological
cancer subtype and the genetic locus that is altered [121].
More recent meta-analyses report an increased risk for gastric cancer with SNPs of the locus IL1β-511T and of IL1RN
only in Caucasians [122–124]. There are further hints of an
association between these SNPs and premalignant changes
of the gastric mucosa, as well as an interaction with polymorphisms of the COX2 gene [125, 126].
Other cytokines which might bear functional relevance of defined haplotypes include IL10 [127, 128],
TNFα [125, 129] and IL8 [130–132]. In most cases (except
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β-catenin release and furthermore modulation of apoptosis and cell cycle regulation [72, 73].
The outer membrane protein BabA (blood group antigen-binding adhesin) mediates the adherence to the
ABO/Lewis b antigen in the gastric pit and is expressed
by 40–95% of the H. pylori strains, also varying by geographic region [74, 75]. Patients infected with a BabApositive strain show a higher density of bacterial colonization in the stomach and enhanced inflammation due to
increased IL8 levels [76]. Although BabA can mediate
epithelial transdifferentiation to IM in response to H. pylori, a clear association to gastric cancer development has
not yet been shown [75, 77]. However, H. pylori strains
expressing all three factors (CagA, VacA, BabA) are associated with the highest risk for developing gastric cancer [78].
The genotype of the recently described factor iceA (induced by contact with epithelium A) might also be associated with gastric carcinogenesis [79, 80], and further H.
pylori risk factors are under investigation with varying
results depending on the method of detection and the
time frame of tissue or blood sampling [81].
IL10), these cytokine polymorphisms result in a higher
secretion of the corresponding cytokine leading to a
stronger Th1-dominant immune response. A meta-analysis of 18 studies on polymorphisms in the IL8 gene revealed an overall increased risk, but this was particularly
remarkable in Asian populations [132]. In contrast, polymorphisms of the IL10 gene seem to have a mainly protective effect concerning gastric cancer development, especially in Asian populations [128]. There is also interaction with other risk factors like H. pylori infection or
smoking tobacco [133].
Intensive research has been performed on polymorphisms of pattern recognition receptors, e.g. Toll-like receptors (TLRs) and nucleotide-binding oligomerization
domain (NOD) receptors [134, 135]. TLR variations may
have a different effect on gastric cancer susceptibility.
Polymorphisms in the TLR1 gene are associated with different gastric diseases including a protective effect against
gastric cancer development (OR 0.4; 95% CI: 0.22–0.72),
and are furthermore related with alterations of downstream cytokine signaling [136]. Results on TLR2 are conflicting, whereas TLR4 alterations seem to increase the
risk for gastric adenocarcinoma and premalignant changes as shown by a recent meta-analysis [137–139]. Both
ethnicity of the respective study population and H. pylori
infection status have an impact on the results of these
analyses [137, 139]. Results on polymorphisms of NOD1
or NOD2 and the effect on related downstream regulation, including NFκB-related signaling, are inconsistent
[117, 135, 140].
activation of major oncogenic pathways include regulators
of stem cell proliferation, NFκB-, and Wnt/β-catenin-related
signaling, and are deregulated in more than 70% of the
analyzed cancer samples [149].
The involved regulatory processes show different patterns depending on the tumor localization. Differences
could be identified for proximal versus distal gastric cancer of the intestinal type, especially when compared with
diffuse-type neoplasias [150, 151]. Lei et al. [152] suggested a stratification into three different gastric cancer subtypes showing not only specific pathobiological characteristics but also remarkable differences concerning the
response to treatment with either 5-fluorouracil or compounds targeting the PI3K-Akt-mTOR axis. These data
may facilitate the design of clinical trials using novel therapeutic agents [153]. Recently, by application of the genome-wide association studies approach, also SNPs in
the TLR1 gene have been identified to determine susceptibility for H. pylori infection [154].
Complex protein level changes can be assessed by
high-throughput techniques like matrix-assisted laser desorption/ionization imaging, and changes shown using
hierarchical clustering or principal component analysis
[155]. The related protein signatures are also capable of
differentiating between tumor types, organ sites and even
biological behavior of metastases and treatment response
[156–159].
Genome-Wide Approach
By genome-wide association studies of structural gene
aberrations or specific expression profiles, classifiers for
diagnostic purposes, an individual prognostic assessment, or a treatment susceptibility profile can be generated [96, 141, 142]. Instead of using de novo data, a computational ‘in silico’ analysis of publicly available (i.e. previously published) data can be performed to generate
target signatures that can be correlated with any tumorspecific feature, like the degree of differentiation, general
tumor stage, or survival and outcome after surgical treatment [143–145]. A focus on genes that are targets of therapeutic compounds (e.g. epithelial growth factor receptor, EGFR, HER2) might allow the prediction of the prognostic outcome with neoadjuvant or even palliative
therapy regimens [146, 147].
A further task is the identification of mechanisms that
make the carcinoma prone to local invasion and/or metastatic spread [148]. Gene expression signatures that lead to
The inflammatory environment in the gastric mucosa
mirrored by the cytokine milieu has a major influence on
the initiation of gastric carcinogenesis (fig. 1). IL1β, mostly
secreted by macrophages and to a lesser extent by epithelial
and dendritic cells, induces the expression of other cytokines such as IL12, TNFα, IL2 and interferons (IFN) that
subsequently shift the immune balance towards a mixed or
Th1-predominant inflammation as it is seen in H. pylorimediated gastritis [160–162]. The subsequent infiltration of
granulocytes and lymphocytic cells leads to a chronic inflammatory condition and lasts as long as the bacterium
colonizes the gastric mucosa. The degree of colonization
and gastritis is dependent on various factors, such as the
presence and activity of regulatory T cells (Tregs) or the
initial (naive) parietal cell mass (which reflects the acid-secreting capacity) [160–165]. Tregs are associated with increasing bacterial colonization [166], chronic inflammatory changes [167, 168] and the expression of immunosuppressive cytokines like IL10, IL17 and TGF-β [163, 169]. In
H. pylori and Gastric Cancer
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Response to H. pylori in the Gastric Mucosa
the case of gastric cancer, Tregs are increased both in the
gastric mucosa and the peripheral blood [170–173]. As
shown by immunohistochemistry, increasing numbers of
FOXP3-expressing CD4+CD25+CD117lowTreg cells are associated with vascular, lymphatic and perineural invasion
of gastric tumor cells, as well as with advanced tumor stage
[174]. The ratio of Th1/Th2-derived cytokines is the highest
in asymptomatic gastritis showing a steady decrease in gastric atrophy, IM and intraepithelial neoplasia progression
to gastric adenocarcinoma. This is associated with a concomitant increase in the Treg cell compartment in the peripheral blood as well as persistence of CagA-positive strains
that favors a Treg-mediated chronic inflammation [170].
When H. pylori infection is predominantly located in
the antrum, the acid secretion is usually unchanged or
can even be increased, resulting in ‘hyperchlorhydria’
which predisposes to duodenal and gastric ulcer formation. If H. pylori colonizes predominantly the gastric
body, the antisecretory effect of IL1β leads to a vicious
cycle by induction of hypochlorhydria which in turn fa254
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cilitates the further spread of H. pylori in the mucosa of
the corpus and fundus. The resulting corpus-predominant inflammation leads to mucosal atrophy and IM. An
additional impact of IL1β is given by its cytoprotective,
antiulcerative effects and capability to modulate gastric
motility and therefore delay gastric emptying [115].
Figueiredo et al. [175] analyzed different CagA and VacA
genotypes of H. pylori strains isolated from patients with
gastric cancer or nonatrophic gastritis in the context of
the presence of an ‘IL1 proinflammatory genotype’, and
identified combinations with either low or high risk for
gastric cancer, resulting in a variable OR of 6–87. The
‘proinflammatory’ genotype is associated with elevated
IL1β levels in the gastric mucosa [176]. The scores for
mucosal atrophy and related gastritis are higher in H. pylori-infected patients with the proinflammatory IL1β-511
T/T genotype which also present with an elevation of the
gastric juice pH as well as decreased pepsinogen I/II ratios
as surrogate for mucosal atrophy [177]. The IL1β genotype seems to have no effect on physiological or histoBornschein /Malfertheiner
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Fig. 1. Mucosal response to H. pylori infection. The inflammatory response of the
gastric mucosa to H. pylori infection and
other cocarcinogens is mediated by a shift
towards a proinflammatory cytokine milieu, which leads to further mucosal damage and finally altered life cycle of the epithelial cells. These processes are enhanced
in the presence of both bacterial virulence
factors (e.g. CagA, VacA) and gene alterations that change the host’s susceptibility to
further malignant tissue transformation.
H. pylori and Gastric Cancer
It is not yet clarified to which extent gastric epithelial
stem cells as well as bone marrow-derived stem cells contribute to the processes mentioned above [202–204]. The
local mucosal environment, like the mucin pattern, has a
further influence on the H. pylori-related response pattern [205].
Eradication of H. pylori for Gastric Cancer Prevention
In a meta-analysis on 6,695 patients, eradication of H.
pylori infection decreased the RR of developing gastric
cancer by 35% [206]. At present, most trials assessing the
preventive effect of H. pylori eradication on gastric cancer
incidence have been undertaken in high-incidence regions
within Asia (table 1). In a prospective interventional study
from Japan, patients with H. pylori-induced peptic ulcer
disease (n = 1,342) were followed for a median of 3.4 years
[207]. Gastric cancer occurred in 0.8% of the successfully
eradicated patients in contrast to 2.3% of patients with
eradication failure [207]. So far, the only prospective, randomized, placebo-controlled primary prevention study
has been performed in China with 1,630 H. pylori-positive
individuals being randomized on either eradication or placebo treatment [208]. Within a follow-up period of 7.5
years, there were 18 new cases of gastric cancer, 7 in the
eradication group and 11 in the placebo group. Subgroup
analysis revealed that all patients with newly diagnosed
gastric cancer presented with preneoplastic changes of the
gastric mucosa (gastric atrophy, IM) at baseline, whereas
no case of gastric cancer was diagnosed in patients without
baseline mucosal changes [208]. In a prospective observational study from Japan (1,787 patients; 9 years’ followup), all patients who still developed gastric adenocarcinoma after eradication presented with severe atrophic gastritis at baseline [209]. The risk of gastric carcinogenesis is
significantly correlated with the degree of baseline atrophy
that is induced by H. pylori-driven inflammation [210,
211]. In a prospective study from Japan, 4,655 healthy,
asymptomatic individuals were followed up endoscopically for 7.7 years presenting an HR for gastric cancer of 7.1
in the case of H. pylori infection without glandular atrophy,
14.9 if both conditions had been detected and 61.9 if H.
pylori infection could not be detected any more due to the
severe atrophic changes of the gastric mucosa [212]. In
multiple logistic regression analysis, degree and distribution of IM have also been demonstrated to be independent
risk factors for gastric cancer development [213]. A nationwide cohort study from the Netherlands, including more
than 90,000 participants, demonstrated a stepwise increase
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logical parameters of gastric mucosa in H. pylori-negative
patients. In a study from Thailand, IL1β-511 TT carriers
had significantly higher IL1β levels in the antrum than
corresponding controls, also influenced by bacterial factors (e.g. CagA type) [178]. In contrast, data from Korea
showed higher mucosal IL1β levels in patients with ‘wildtype haplotype’ compared to those with ‘proinflammatory haplotype’ [179].
The immune response can be modulated by further
mechanisms. H. pylori-induced activation of NOD1 can
lead to higher expression of IL8- and IFNγ-related signaling [180]. An increased gene expression of IL8, IL10 and
TNFα that is induced by H. pylori-dependent TLR activation has been shown in adult patients with gastritis or
further advanced diseases stages but also already in children positive for the infection [181–183]. These processes are mainly NFκB mediated, also leading to an increase
in IL32 levels in a cagPAI-dependent manner [136, 182,
184]. Functional relevance has been attributed to CagL
which can regulate the host’s production of IL1β via TLR2
and NOD2 activation [185].
These inflammatory processes are also related to the
induction of certain transcription factors (e.g. CDX2) in
the gastric mucosa that lead to transdifferentiation into
spasmolytic polypeptide-expressing metaplasia or IM
[186–188]. RUNX3 is deregulated in IM by tyrosine phosphorylation due to CagA-induced c-Scr activation leading to reduced expression at both the mRNA and protein
levels [189, 190]. Downstream signaling involves ERK/
mitogen-activated protein kinase pathways that are also
involved in the activation of the gastrin promoter by
CagA [191]. Further induction of gastrin expression is
mediated by CagL binding to an integrin-αvβ5/integrinlinked kinase complex of the host [192]. Gastrin itself is
important for homeostasis in the intact gastric mucosa,
and it has a complex role in gastric carcinogenesis, including the mediation of proliferation, angiogenesis and
tissue invasion [193]. The gastrin receptor expression is
increased in H. pylori gastritis [194] partly due to an IL1βinduced downregulation of gastrin and histamine levels
in the stomach to inhibit acid secretion from parietal cells
[115, 195, 196].
A further effect of epithelial contact with the cagPAI
type IV secretion system is higher expression of the EGFR
and its activation leading to downstream activation of
COX2 [197, 198]. This is accompanied by a shift towards
a proapoptotic homeostasis with increased expression of
bax and decreased expression of bcl2 [199, 200]. The induction of oncogenes like cmyc is also interfering with
these processes [199, 201].
Table 1. Effect of H. pylori eradication on gastric cancer incidence and preneoplastic conditions
First author
Year
Country
End point: regression atrophy/IM
Ruiz [237]
2001 Colombia
Schenk [220] 2000
Study
type
Population
prosp.
cohort
132
Netherlands prosp.
cohort
China
case
control
57
Lu [238]
2005
Lee [239]
2013
Taiwan
You [240]
2006
China
Ito [241]
2002
179
case
control
prosp.
cohort
2,603
Japan
prosp.
cohort
22
Yamada [242] 2003
Japan
116
Ohkusa [224] 2001
Japan
Cho [218]
Korea
prosp.
cohort
prosp.
cohort
prosp.
cohort
case
control
80,255
case
control
prosp.
cohort
prosp.
cohort
268
2013
End point: GC incidence
Wu [226]
2009 Taiwan
3,365
163
190
Maehata [243] 2012
Japan
Zhou [244]
2005
China
Wong [208]
2004
China
Saito [245]
2000
Japan
Uemura [216] 1997
Japan
Fukase [227] 2008
Japan
prosp.
cohort
544
Take [210]
2007
Japan
1,131
Uemura [8]
2001
Japan
Kamada [209] 2005
Japan
Leung [246]
2004
China
Sung [217]
2000
China
prosp.
cohort
prosp.
cohort
prosp.
cohort
prosp.
cohort
prosp.
cohort
prosp.
cohort
prosp.
cohort
552
1,630
64
132
1,526
1,787
435
587
Groups
Follow- Outcome
up, years
Special characteristics
treatm. 29; control 82 6.0
regression of atrophy
successful erad. 33;
erad. failure 24
treatm. 92;
control 87
1.0
no change in atrophy
1.8
regression of atrophy (–28.26%);
IM with mixed results
treatm. 841;
control 1,762
Hp erad., vitamin
supplements, garlic
extract
one arm
13.0
regression of atrophy (–77.2%);
no change in IM
only positive effect on regression
of severe atrophy
successful erad. 87;
erad. failure 29
successful erad. 115;
erad. failure 48
active treatm. 95;
placebo 95
1.8
‘early erad.’ 54,576;
‘late erad.’ 25,679
7.3
5.0
morphometric
analogue
scale evaluation
–
partly regression/
progression also for
controls
5 year interval assessment
–
regression of atrophy (antrum,
corpus); regression of IM (antrum,
corpus)
regression of atrophy (corpus);
no change in IM
regression of atrophy (–89%, corpus);
regression of IM (–61%, antrum)
regression of atrophy (–58.6%);
regression of IM (–60.5%) by erad.
–
5.9 – 7.2
GC incidence: 136/54,576 (2.5%)
vs. 113/25,679 (4.4%)
treatm. 177;
control 91
Hp neg. 246;
Hp pos. 306
active treatm. 817;
placebo 813
3.0
GC incidence: 15/177 (8.5%) vs.
13/91 (14.3%)
GC incidence: 1/246 (0.4%) vs.
5/306 (1.6)
GC incidence: 7/817 (0.9%) vs.
11/813 (1.4%)
eradication after peptic
ulcer; ‘early’: within 1
year, HR 0.77
–
treatm. 32;
control 32
treatm. 65;
control 67
2.0
treatm. 255;
control 250
3.0
successful erad. 953;
erad. failure 178
Hp neg. 280;
Hp pos. 1,246
one arm
3.9
treatm. 220;
control 215
active treatm. 295;
placebo 292
5.0
1.3
3.0
5.0
7.5
3.0
7.8
9.0
1.0
–
–
intervention after
subtotal gastrectomy
population-based study
no GC in subgroup
without preneoplastic
conditions
GC incidence: 0/32 (0%) vs.
progression of gastric
4/32 (12.5%)
adenoma
GC incidence: 0/65 (0.0%) vs.
end point:
6/67 (9.0; IM regression after 2 years) metachronous
GC after EMR for EGC
GC incidence: 9/255 (3.5%) vs.
end point:
24/250 (9.6%)
metachronous
GC after EMR for EGC
GC incidence: 9/953 (0.9%) vs.
risk increase for GC
4/178 (2.2)
with baseline atrophy
GC incidence: 0/280 (0%) vs.
–
36/1,246 (2.9%)
GC incidence: 20/1,787 (1.1%)
all GC patients with
severe baseline atrophy
IM progression: 41.3 vs. 60.1%
H. pylori persistence as
negative predictor
regression of IM in antrum
–
256
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DOI: 10.1159/000357858
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EGC = Early gastric cancer; EMR = endoscopic mucosal resection; erad. = eradication; GC = gastric cancer; Hp neg./pos. = H. pylori negative/positive;
prosp. cohort = prospective cohort study; treatm. = eradication treatment.
Point of no return?
Chronic
atrophic
gastritis
H. pylori
infection
IM
Dysplasia
Intestinal
type
Growth factors
HIF1į9(*)(*)3'*),*)
Inflammation
IL1DŽ,/,/71)į,)1Dž
,/7*)DŽ
Chronic
active
gastritis
Transcription factors
&';&'; 7))
62;
Oncogenes
Tumor suppressor genes
FPHWFP\F
Gastric
cancer
$3&SSS581;)+,7
Invasion-related factors
003003003
(FDGKHULQ
Diffuse
type
nogenesis. There are two major histological types of gastric adenocarcinoma, the intestinal and the diffuse type. Both are associated
with H. pylori infection and certain pathobiological mechanisms
including the activation of growth factors, a shift of certain transcription factors and an imbalance in tumor suppressor genes and
oncogenes. The development of intestinal-type cancer follows distinct steps of histopathological changes of the mucosa. However,
this sequence does not necessarily have to be complete or follow
the specific order indicated here. No precursors of diffuse-type
cancers are currently known.
in gastric cancer incidence within 5 years’ follow-up that
was 0.1% in patients with chronic atrophic gastritis, 0.25%
in patients with IM, 0.6% in the case of mild or moderate
dysplasia and 6% in the case of severe dysplasia at baseline
assessment (HR 40.1; 95% CI: 32.2–50.1) [214].
What defines the point of no return, when eradication
of H. pylori will no longer prevent further progression of
IM and atrophic gastritis towards gastric cancer [215]?
Several trials assessed to which degree preneoplastic
changes could be reversed by H. pylori eradication. The
degree of IM decreased after eradication therapy in patients endoscopically or surgically treated for early gastric
cancer in a 3-year follow-up [216–218]. The data about
the actual regression of IM or glandular atrophy are controversial. Several authors report an improvement only of
the degree of inflammation within one year after eradication but no effect on metaplasia or atrophy [219, 220].
Rokkas et al. [221] presented a meta-analysis on the longterm effect of eradication therapy on gastric histology.
The risk associated with atrophic gastritis was reduced by
45% in total (OR 0.55; 95% CI: 0.37–0.83), and by almost
80% for alterations in the gastric body (OR 0.21; 95% CI:
0.08–0.54). An influence on IM could not be confirmed
in this study or in a recent meta-analysis of 12 studies
[222] which showed that eradication of H. pylori led to
significant improvement of atrophy in the gastric corpus,
but not in the antrum, and to no improvement of IM.
However, in this analysis the degree of mucosal changes
is not mentioned, which is crucial since only extensive
atrophic alterations impact on gastric function. A recent
study from Taiwan demonstrated a reduction of atrophic
changes by 77.2% after population mass eradication without a significant effect on IM prevalence [223]. In the
same observation period, gastric cancer incidence was reduced by 25%.
It has been suggested that the decisive factor whether
or not H. pylori eradication has an effect is the length of
follow-up since an improvement of mucosal inflammation can be documented within the first 6–12 months after eradication; however, a follow-up period of more than
one year is necessary to demonstrate an effect on IM and
atrophic changes [224, 225]. The site of biopsy sampling
may also be an important factor [225].
The point of time at which H. pylori eradication can
still contribute to gastric cancer prevention remains the
burning question in this debate (fig. 2). In a cohort study
of 80,255 patients, the risk for gastric cancer development
was smaller with earlier H. pylori eradication after peptic
H. pylori and Gastric Cancer
Dig Dis 2014;32:249–264
DOI: 10.1159/000357858
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Fig. 2. Histopathological and molecular changes in gastric carci-
ulcer disease. Compared to the general population, patients that received early H. pylori eradication had no increased gastric cancer risk [226]. Even after endoscopic
resection of early gastric adenocarcinoma, recurrence of
metachronous gastric cancer is significantly reduced by
H. pylori eradication [227]. A recent retrospective analysis on 268 H. pylori-positive patients after endoscopic
cancer resection could not confirm these results [228].
However, the period of follow-up was identified as an independent risk factor.
Conclusions
H. pylori represents the main carcinogen in gastric neoplasia. For an individual risk assessment, the interaction
between bacterial virulence factors and the host’s susceptibility profile must be taken into account. In spite of the
proof that H. pylori eradication is effective in gastric cancer prevention in several studies, an ultimate study on a
large population and a considerably longer observation
time would convince all those who are reluctant to include
H. pylori eradication in preventive strategies [229, 230].
In addition, a close and effective endoscopic follow-up
and surveillance are mandatory in the case of present mucosal alterations at baseline assessment, even after successful H. pylori eradication [231–233]. Although this has
already been recommended in European consensus guidelines [234, 235], it will be a matter of debate if this approach can be considered as cost-effective in low-incidence regions like central Europe or North America [236].
Disclosure Statement
The authors declare that no financial or other conflict of interest exists in relation to the content of the article.
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