1. Introduction
Different outcomes of
The outcome of
2. Helicobacter pylori virulence factors
2.1. cagA
There are two types of clinical
CagA protein is composed of a disordered C-terminal region that contains the EPIYA motifs and a structured N-terminal region with several conserved regions. When the bacterium contacts the host cell CagA is injected into the host cell via the
Recently it was demonstrated that another protein component of T4SS termed CagL induces hypergastrinemia, which is a major risk factor for the development of gastric adenocarcinoma [17].
2.2. vacA
VacA induces vacuolation of the host cell, membrane-channel formation, cytochrome
The most cytotoxic are s1/m1 strains, followed by s1/m2 strains, whereas s2/m2 strains have no cytotoxic activity and s2/m1 strains are rare [24]. Individuals infected with s1 or m1
Intermediate region of
The deletion (d) region—was identified between the i-region and the m region [26]. The d region is divided into d1 and d2. The study of Western strains demonstrated that d1 was a risk factor for gastric mucosal atrophy; however, almost all East Asian strains are classified as s1/i1/d1 [11].
2.3. oipA
Outer membrane proteins (OMPs) are coded by different genes in
OipA is a protein that induces proinflammatory response and its activity leads to increase in mucosal interleukin-8 (IL8) levels. OipA is involved in the attachment of
The production of CagA, VacA and OipA is linked and the majority of
2.4. dupA
Duodenal ulcer–promoting gene
2.5. Geographic differences in gastric cancer incidence related to Helicobacter pylori strains
Multilocus sequence typing (MLST) of the housekeeping genes revealed six
Sequence differences among the examined housekeeping genes of the six major genotypes probably have no influence on the disease outcome but serve as a marker for other virulence factors related to the disease outcome (i.e
Populations with high rates of gastric cancer correspond with regions presenting hpEastAsia strains. In contrast, incidence of gastric cancer is very low in Africa, where most strains are hpNEAfrica, hpAfrica1 or hpAfrica2, and in South Asia, where most strains are hpAsia2. The differences in
3. Host factors
Host characteristics and immune response to
4. Cytokine gene polymorphisms
Cytokines modulate inflammatory response to
4.1. Interleukin-1
Interleukin-1 beta (IL-1β) is a potent inhibitor of gastric acid secretion. Reduced gastric acid secretion on the other hand promotes development of
Results of meta-analysis provided by Persson et al. based on available data from epidemiological studies showed strongest association of IL1RN2 polymorphism with increased risk for gastric cancer [35] in non-Asian populations for both intestinal and diffuse cancers. The
4.2. Tumor necrosis factor alpha
Tumor necrosis factor alpha (TNF-α) is another proinflammatory cytokine produced in gastric mucosa in response to
4.3. Interleukin 10
Interleukin 10 is an anti-inflammatory cytokine that down-regulates
4.4. Interleukin 8
IL-8 is a CXC family cytokine that is a potent chemoattractant for neutrophils and lymphocytes affecting proliferation, migration, and tumor angiogenesis. However, not all studies have replicated the positive associations between pro-inflammatory cytokines polymorphisms and gastric cancer risk [42]. A polymorphisms in
4.5. Presence of multiple high-risk cytokine gene polymorphisms
Possession of multiple high-risk host polymorphisms is associated with increased risk for gastric cancer. Presence of 3-4 of the polymorphisms (
5. Polymorphisms in innate immune response genes
5.1. Toll like receptor 4 (TLR4)
TLR4 is a cell-surface signaling receptor involved in the recognition and host response to
6. Cell proliferation-related gene polymorphisms
Meta-analysis by Gao et al identified 23 polymorphisms significantly related to gastric cancer in at least one published study suggesting the importance of polymorphisms in genes implicated in cell proliferation in development of gastric cancer. The overall effect of these polymorphisms is probably modest but should not be neglected [46].
6.1. Cell cycle and apoptosis regulators
Cell cycle and apoptosis regulators are directly involved in the initiation of malignant proliferation of the cell. Polymorphisms of functional regulators of
PPAR-γ (peroxisome proliferator-activated receptors γ) is a member of the nuclear hormone receptor family that plays an important role in cell differentiation and regulation of metabolism. A potential interplay between
6.2. Growth factors and growth factor receptors
Polymorphisms determining higher level of growth factors and related receptors, which are important for tissue repair, were associated with reduced risk of gastric cancer. Such associations were observed for gene encoding epidermal growth factor (EGF)
7. Environmental factors
Environmental regulation of virulence factors could be an interesting concept explaining why not all infected individuals develop severe complications of disease despite infection with pathogenic
Recent study demonstrated that high salt diet could influence
7.1. Diet
In 2007 World Cancer Research Fund declared that high intake of vegetables and fruit probably decrease risk of gastric cancer, and that high intakes of salt and salty food probably increase risk of gastric cancer [54]. The proposed underlying mechanism for the inverse association of gastric cancer risk with vegetable and fruit/rich diet is related to the presence of antioxidants. Salt on the other hand acts directly on the stomach lining, destroying the mucosal barrier, causes gastritis and increased epithelial cell proliferation [55]. A synergistic interaction between diet and
7.2. Smoking
Tobacco smoking is the risk factor associated with the largest number of cancer cases worldwide and the causal link with stomach cancer is recognized [54]. A recent meta-analysis found significant positive associations of smoking with risk of both cardia and non-cardia gastric cancer among the majority of studies, overall increasing risk by 62% for male and 20% for female current smokers [57]. It is possible that tobacco smoke carcinogens affect gastric cancer risk directly through contact with the stomach mucosa or indirectly through the blood flow [54]. In a large population-based study in Europe (EPIC), 17.6% of gastric cancer cases were attributed to smoking [56]. The cancer risk in past smokers can remain up to 14 years after cessation of smoking [57,58]. The effect of smoking on gastric cancer is dose-dependent and additive in the presence of other risk factors [59,60]. However, passive smoking does not seem to increase the risk [61].
7.3. Non-steroidal anti-inflammatory drugs
Protective effect of regular use of non-steroidal anti-inflammatory drugs (NSAIDs) and particularly aspirin on risk of gastric cancer was repeatedly reported in observational studies and then results of meta-analysis [62] confirmed these finding. According to Algra et al regular NSAID users have up to 20% reduced risk of gastric cardia adenocarcinoma and up to 36% reduced risk of distal gastric adenocarcinoma [62]. NSAIDs suppress the production of cyclooxygenase enzymes. Data on clinical efficacy of NSAIDs in prevention of gastric cancer first suggested that aspirin reduces risk for both proximal and distal gastric cancer [63]. Recent results from population-based intervention trial by Wong et al revealed that celecoxib treatment or
7.4. Socioeconomic status
Lower socioeconomic status is associated with at least two-fold greater risk of gastric cancer irrespective of the country incidence of gastric cancer [54]. Possible explanation is related to increased likelihood of transmission and re-infection with
8. Importance of Helicobacter pylori eradication in prevention of gastric cancer development-current knowledge and evidence
Histologically gastric cancer is, according to Lauren classification, divided into two subtypes: intestinal and diffuse type. The intestinal type is related to corpus-predominant gastritis with intestinal metaplasia and is closely related to long-lasting
Intestinal type gastric adenocarcinoma results from a prolonged precancerous process. The link between gastric intestinal metaplasia and cancer was proposed by pathologists in Java and Sumatra in 1938. This idea was over time only occasionally revisited by scientists until in 1975 Correa et al proposed a model of gastric carcinogenesis. This model postulated that intestinal type of gastric cancer was a result of progressive changes in the gastric mucosa [68]. Authors updated their model in 1988 and 1992. In Correa cascade the following consecutive steps are now recognized: normal gastric mucosa, superficial (non-atrophic) gastritis, multifocal atrophic gastritis (MAG), complete (small intestine type) intestinal metaplasia followed by intestinal metaplasia of the incomplete (colonic) type, low-grade dysplasia, high-grade dysplasia and invasive adenocarcinoma. [7-9, 68]. Loss of normal glandular tissue is the first specific recognizable step in the precancerous cascade. However, the changes of the precancerous lesions over time remain an issue difficult to assess leading to the fact that the point of no return, although of critical importance for timely eradication, still remains unidentified.
Five randomized controlled trials (RCT) reported effects of
Study by Wong et al. was designed as RCT conducted in a high-risk gastric cancer region in China that evaluated gastric cancer incidence as a primary outcome [69]. Authors identified healthy individuals with
Other above cited trials were not designed to assess gastric cancer as a primary outcome [70, 71] or had low numbers of gastric cancer cases [69, 72] to provide an informative assessment of the effects of eradication on cancer occurrence. Nevertheless, recently an important study was published by Ma et al [74] with the long-term follow-up results of a randomized trial in which 2258
This year Lee et al [76] evaluated the benefit of mass eradication of
Over a decade ago Uemura et al. [77] first reported that
Some years later, Fukase et al. [75] reported the results of a trial in which more than five hundred patients in Japan who had previously undergone endoscopic resection for treatment of early gastric cancer were randomized to either
The evidence from more recent trial reports [74-76], taken together with the epidemiological and experimental evidence for the carcinogenic activity of chronic
9. Conclusion
Higher risk for gastric cancer might be modulated by an overall pro-inflammatory host genetic profile in the adaptive and innate immune systems genes (e.g.
Therefore timely eradication of
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