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Mobley HLT, Mendz GL, Hazell SL, editors. Helicobacter pylori: Physiology and Genetics. Washington (DC): ASM Press; 2001.

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Helicobacter pylori: Physiology and Genetics.

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Chapter 40Gastric Cancer

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Nearly 20 years have elapsed since the discovery of Helicobacter pylori (168). Due to the progress of research during this period, a causal link between H. pylori and gastric mucosal lesions seems almost certain. Experimental ingestion of H. pylori demonstrated that it caused gastritis in humans, with the inflammation being cured by eradication of the organism (103, 109). Furthermore, H. pylori infection is one of the major causes of recurrent peptic ulcer disease (124, 164). Accordingly, patients with peptic ulcer disease are advised to undergo H. pylori eradication therapy.

Gastric cancer is one of the most common malignancies in the world, although the incidence and mortality rate have been decreasing in recent decades. The association between H. pylori and gastric cancer has attracted great interest worldwide because the International Agency for Research on Cancer (IARC), a subordinate organization of the World Health Organization (WHO), identified H. pylori as a "group 1 (definite carcinogen)" in 1994 (1). That is, the IARC concluded that H. pylori was certainly linked to carcinogenesis on the basis of the results of epidemiologic studies.

The association between H. pylori and gastric cancer may be explained by two possible mechanisms: one is based on a carcinogenesis-promoting effect of H. pylori itself and the other is based on the establishment of a carcinogenic environment due to long-term infection with H. pylori. In the second case, although H. pylori may have no carcinogenesis-promoting effect itself, infection causes inflammation of the gastric mucosa and chronic infection causes mucosal atrophy, resulting in intestinal metaplasia. These latter changes are considered precursors of gastric cancer.

Research concerning the association between gastric cancer and H. pylori has achieved enormous progress over time, leading to the recognition of this relationship by the WHO. One of the greatest concerns is to ascertain whether ultimately H. pylori-induced gastritis may lead to gastric cancer. The onset of gastric cancer can be explained as being caused not only by H. pylori infection, but also by a combination of various factors such as food and the environment. However, the possibility that the occurrence of gastric cancer, like the recurrence of peptic ulcer disease, can be prevented by eradication of H. pylori has also been suggested. Further progress in epidemiologic research is needed to resolve this issue.

Epidemiological Evaluation of the Relationship between H. pylori Infection and Gastric Cancer

Persistent H. pylori Infection and Atrophic Gastritis and Intestinal Metaplasia

It has been reported that superficial gastritis progresses to atrophic gastritis after 10 years or more, that atrophy extends from the pyloric glands to the fundic glands of the gastric body over time, and that intestinal metaplasia appears after another 10 years or so (86, 93, 136). In view of the close association between H. pylori infection and histological gastritis, it is conceivable that infection with this organism may be related to the cause of atrophic gastritis and intestinal metaplasia. A prospective study by Kuipers et al. showed that H. pylori infection contributes to the progression of superficial gastritis to atrophic gastritis and intestinal metaplasia (94). They observed 49 patients who were negative for H. pylori and 58 patients who were positive and determined the incidence of atrophic gastritis and intestinal metaplasia over 10 to 13 years. Such pathologies were noted in 2 patients (4%) from the H. pylori-negative group versus 16 patients (28%) from the H. pylori-positive group. This finding indicated that H. pylori infection was involved in the progression to atrophic gastritis and intestinal metaplasia. Similar results were reported by Sakaki (134). In contrast, Niemela et al. conducted a 10-year follow-up study and reported persistent infection in 87% of the patients with gastritis, although there was no progression of atrophy (113). When patients with gastric ulcer were compared instead of patients with gastritis, however, an increased severity of gastritis at the pyloric antrum and an increased incidence of intestinal metaplasia were noted in the H. pylori-positive patients (114). This finding may suggest that the H. pylori strain causing gastric ulcer is likely also to cause gastric mucosal atrophy and intestinal metaplasia. In Japan, asymptomatic individuals were randomly selected from among persons undergoing multiphasic health screening, and gastric biopsies were taken. Biopsy findings were then compared with the levels of serum antibodies. Interestingly, there was no severe atrophy or intestinal metaplasia in subjects who tested negative for H. pylori antibodies (Table 1). When the subjects were stratified by age, there was age-related progression of gastric mucosal atrophy in H. pylori antibody-positive subjects, whereas the antibody-negative subjects showed little mucosal atrophy and no intestinal metaplasia (4). These results indicate that gastric mucosal atrophy in the Japanese population that has been considered a manifestation of aging is strongly influenced by infection with H. pylori. If no infection occurs, progression of gastric mucosal atrophy in Japanese individuals may be as gradual as that in Europeans or Americans.

Table 1. Comparison of gastric mucosal lesions and serum parameters between H. pylori IgG antibody-positive and -negative asymptomatic personsa.

Table 1

Comparison of gastric mucosal lesions and serum parameters between H. pylori IgG antibody-positive and -negative asymptomatic personsa.

Intestinal metaplasia is closely related to atrophic gastritis and gastric cancer, but it occurs in a minority of people with H. pylori infection; the majority remain asymptomatic throughout their lives (14, 24, 163). This phenomenon tends to be more notable in developing countries than in the developed countries. In developing countries, the rate of infection with H. pylori exceeds 80% from infancy, but the proportion of asymptomatic patients is overwhelmingly high (47, 48) and the incidence of intestinal metaplasia or gastric cancer can be relatively low (64). One explanation for this phenomenon may be based on a difference in toxicity among H. pylori strains. Wyle suggested that infection with H. pylori always caused acute gastritis and nonatrophic chronic gastritis, but the subsequent course varied with the strain of H. pylori; e.g., some strains may cause duodenal ulcer disease and others cause gastritis that proceeds to gastric cancer through gastric mucosal atrophy (172). Unfortunately, the antibody assays currently used in epidemiologic studies cannot determine differences among H. pylori strains. Methods for distinguishing differences in toxicity among strains may be developed in the future. Differences in the severity of gastric mucosal damage due to strain differences could be an important factor but do not provide a complete explanation for individual differences of H. pylori infection-induced gastric mucosal injury. In fact, it has been found that the severity of infection varies with differences in host factors. Among the reports on host factors and the progression of atrophic gastritis, Beales et al. have emphasized the role of HLA-DQ type (11).

Another factor determining the severity of gastric mucosal injury is the time of onset of H. pylori infection. When H. pylori infection occurs in neonates and infants, it leads to pangastritis that extends throughout the stomach, often because acid secretion is insufficient. In addition, when atrophy of the fundic glands is caused by persistent inflammation, the parietal cells are disturbed and this can lead to hypoacidity (7). Intestinal metaplasia occurs when atrophy progresses further. On the other hand, when H. pylori infection occurs after the neonatal period or infancy, the development of parietal cells is already complete, so acid secretion is normal and it is difficult for the organism to survive in the fundic glands (9, 52). Therefore, H. pylori colonizes the pyloric antrum and causes antral gastritis. Accordingly, there is damage to the background mucosa in addition to normal acid secretion, conditions that suggest a high risk of peptic ulcer disease.

As described above, individual differences in gastric mucosal injury due to H. pylori infection are probably determined by differences between strains, variations in host immunity, and differences in the timing of infection (92).

Long-Term H. pylori Infection: from Gastritis to Gastric Cancer

The association between H. pylori and gastric cancer has been explained by two possible mechanisms. One is that H. pylori may have no carcinogenic effect per se, with infection inducing inflammation of the gastric mucosa that eventually leads to atrophy and intestinal metaplasia (18, 136). The other is that H. pylori may synthesize or modify compounds having carcinogenic properties. We need to determine whether H. pylori infection produces an unknown chemical initiator during the process of gastric carcinogenesis or directly acts as a promoter. Because H. pylori cannot reduce nitrites (28), it may not be a source for the direct production of nitroso compounds and no evidence has been presented to indicate that the concentration of N-nitroso compounds in gastric juice is increased in H. pylori-positive patients with chronic gastritis (150).

Gastric mucosal infection with H. pylori is accompanied by infiltration of neutrophils, and activated inflammatory cells are known to produce oxygen radicals (36, 129, 154). Davis et al. have reported an increase of oxygen radical production in both the duodenal and gastric pyloric mucosa after infection with H. pylori (26). Oxygen radicals are known as inducers and initiators because they cause direct DNA damage (17), but the relationship of these radicals with the onset of gastric cancer has not been sufficiently explored. Ammonia/ammonium concentrations increase in the gastric mucosa due to infection with H. pylori, and Tsujii et al. have found that ammonia acts as a promoter in a rat model of gastric cancer induced by N-methyl-N-nitro-N-nitrosoguanidine (MNNG) (161). Ascorbic acid is known to react with nitroso compounds derived from nitrous acid, which produces nitric oxide, thereby inhibiting the formation of N-nitroso compounds (91). The gastric juice concentration of ascorbic acid is decreased in patients who are positive for H. pylori, and it has been demonstrated that H. pylori eradication brings about an increase in the secretion of ascorbic acid into gastric juice (23, 151, 178). As has been mentioned, many questions remain to be resolved about infection with H. pylori. However, it has become evident that there are many mechanisms that cause a variety of chemical changes in both gastric juice and the gastric mucosa, providing an explanation for the association of H. pylori with the onset of gastric cancer (177).

In 1994, the IARC/WHO identified H. pylori as a group 1 carcinogen (1). In the WHO classification, substances are classified into four groups that range from group 1 (definite) to group 4 (not a carcinogen). Like tobacco smoking and hepatitis B virus, H. pylori was classified as group 1, i.e., as having a certain relationship to carcinogenesis. Generally, to attain a group 1 classification experimental data, in addition to epidemiologic data, are required. In the case of H. pylori, however, the classification was assigned on the basis of epidemiologic data alone.

Epidemiologic investigations on the positive association between H. pylori and cancer date from 1991 when successive studies conducted on large numbers of subjects were published (43, 115, 121). Since these were prospective studies, the findings were very persuasive and had a strong impact on subsequent investigations. In 1993, a comparison of H. pylori antibody prevalence between young and old patients in various countries, who were matched for the incidence and mortality rate of gastric cancer, was reported. The countries in which asymptomatic patients showed a high prevalence of H. pylori antibody also had high morbidity from gastric cancer (34). On the other hand, Rudi et al. compared the prevalence of H. pylori antibody in 111 patients with gastric cancer and 111 patients with large bowel cancer, matched with respect to age and sex (133). They reported that the prevalence of antibodies to H. pylori was 58.6% in the gastric cancer patients and 50.5% in the bowel cancer group, with no significant difference between them.

As has been mentioned, investigators are divided as to whether the prevalence of H. pylori antibody is higher in patients with gastric cancer than in controls. To address this point, we collected serum samples from 213 cancer patients in different districts of Japan (Sapporo, Niigata, Tokyo, and Osaka) and determined the H. pylori antibody titer in these serum samples as well as in samples from an identical number of healthy persons (samples collected mainly at multiphasic health screening centers) who matched the patients with respect to age and sex. The prevalence of H. pylori antibody was much higher in the gastric cancer patients (88.2%) than in the controls (74.6%). When the odds ratio was calculated, the highest value (4.9) was obtained in patients with early gastric cancer, and patients with advanced cancer showed an odds ratio of 1.9. These values did not differ significantly from those of the control group. When the H. pylori antibody titer and the tumor histology were compared with respect to the odds ratio, only the odds ratio (4.0) for an intestinal type of early gastric cancer was higher than that for the serum H. pylori antibody titer in patients without cancer. These findings suggest that infection with H. pylori mainly causes an intestinal type of early gastric cancer via the sequence of acute gastritis, atrophic gastritis, and intestinal metaplasia (6).

Similar results were reported by Fukuda et al. (46), who found that the odds ratio was increased when all subjects had a serum pepsinogen I to II ratio of 3 or less, a criterion that took into consideration the possibility of a false-negative result for H. pylori antibodies, owing to severe gastric atrophy. These findings are highly suggestive of the possibility that H. pylori infection is mainly associated with an intestinal type of early gastric cancer and that progression occurs via gastritis, atrophic gastritis, and intestinal metaplasia, in that order. Since intestinal metaplasia becomes increasingly extensive before early gastric cancer progresses to advanced cancer, it is inferred that H. pylori almost completely disappears from the stomach as a result and the antibody titer decreases. Accordingly, the difference in opinion about the association between the prevalence of H. pylori antibodies and gastric cancer is considered to be due to the study population containing a large percentage of patients with advanced cancer. Thus, the natural history of gastric cancer is consistent with progression from H. pylori infection through chronic gastritis, chronic atrophic gastritis, intestinal metaplasia, and early gastric cancer to advanced cancer (8).

In developing countries and Japan, the prevalence of H. pylori antibody in asymptomatic controls may exceed 70% (7, 52, 53). Consequently, it has been suggested that one reason why there is no significant difference in the prevalence of H. pylori antibody between gastric cancer patients and controls is the high prevalence in the controls (70). Kikuchi et al. investigated younger patients with gastric cancer (83). Patients aged 34 years on average were compared with age- and sex-matched controls. Data generated from this study indicated a strong relationship between H. pylori infection and gastric cancer, with a high odds ratio of 13.3. This result showed the potent association between H. pylori infection and gastric cancer in young patients who predominantly have a diffuse type of gastric cancer.

It is evident from various findings reported so far that acute inflammatory cell infiltration into the gastric mucosa is caused by infection with any H. pylori strain (8). The course of this process is considered to vary with the H. pylori strain or the immune response, thereby leading to a difference in the severity of gastric mucosal inflammation. Chronic inflammation due to the long-term persistence of H. pylori infection is considered to lead to gastric mucosal atrophy, although it may vary considerably in severity (42, 71). The occurrence of intestinal metaplasia, for which a relationship to gastric cancer has been strongly suggested, is demonstrated in approximately 60% of persons with H. pylori infection (4, 5). This suggests that there is unlikely to be major differences among strains or in relation to the host immune response. Since the serum antibody titer is considered to reflect both of these factors, it may be said that a high antibody titer indicates severe gastric mucosal inflammation and that its long-term persistence is likely to cause metaplasia of the gastric mucosa (30, 102). Environmental factors (e.g., diet) and genetic factors may also participate in this progression to intestinal metaplasia (160). Metaplasia may then progress to gastric cancer, especially to tumors that are of the intestinal type (Fig. 1) (8). Recently, Shimizu et al. conducted a carcinogenesis experiment by infecting Mongolian gerbils with H. pylori and reported that progression to gastric cancer was chiefly seen in animals that showed a high H. pylori antibody titer (145).

Figure 1. Association of H.

Figure 1

Association of H. pylori infection with development of gastric cancer. (Reprinted from reference with permission.)

To consider the association between H. pylori infection and the onset of diffuse type of gastric cancer, unlike intestinal type gastric cancer, the process from infection with H. pylori through gastric mucosal atrophy, intestinal metaplasia, and development of cancer must be excluded (20, 40). Direct evidence must therefore be found to indicate progression from infection with H. pylori through persistent inflammatory cell infiltration resulting in DNA damage by oxygen radicals, point mutations of genes, and finally carcinogenesis.

As has been discussed, there is little doubt that persistent infection with H. pylori is closely related to the development of gastric cancer. However, if we assume that the number of Japanese infected with H. pylori is around 60,000,000, gastric cancer arises in only 0.4% of them per year, because the number of patients with gastric cancer was 235,000 in 1993 (2). This finding suggests that factors other than H. pylori are involved in the onset of gastric cancer. A conventional approach that only looks at the H. pylori strain and host factors will not suffice. It might be reasonable to consider that gastric cancer is caused by a combination of the effects of various factors in addition to H. pylori. However, when the incidence of gastric cancer is assessed epidemiologically, the lifetime morbidity is not expressed by a single rate, but by the cumulative rate. According to the 1997 report of the IARC, the probability of suffering from gastric cancer between the ages of 0 and 74 in Japan is estimated to be 6.5% on average (120). When the odds ratio of 4.9 that we found for H. pylori infection in patients with early gastric cancer (8) is applied to this estimate, the lifetime morbidity from gastric cancer is estimated to be 2.2% for persons not infected with H. pylori and 10.8% for infected persons, being far higher in the infected group.

As described later, an association between H. pylori infection and gastric cancer has not only been shown by epidemiologic investigation, but also by animal experiments. Eradication of H. pylori can prevent peptic ulcers from recurring, so eradication also seems likely to prevent gastric cancer from occurring. Uemura et al. studied two groups of patients who underwent endoscopic mucosal resection for early gastric cancer (162). Of these two groups, one underwent treatment to cure their H. pylori infection and the other did not. After a 5-year follow-up period, no second cancer occurred in the H. pylori eradication group, whereas 9% of patients in the noneradication group had a second cancer. However, there have been no other papers reporting that H. pylori eradication prevents gastric cancer.

Because a large percentage of the population is infected with H. pylori around the world, its eradication from all infected persons is not practical. Important data are needed, for example, on whether gastric mucosal atrophy and intestinal metaplasia are reversible and whether reversibility is influenced by age, sex, or severity to determine the indications for H. pylori eradication. However, there seems to be little doubt that in the future the incidence of gastric cancer is very likely to depend on how the indications for H. pylori eradication are established. Therefore, the expectations are that research in this field will provide important data necessary to the management of H. pylori infection and the identification of those at greatest risk of developing gastric cancer.

Molecular Pathogenesis of H. pylori and Gastric Cancer

An association of H. pylori and gastric cancer and recent studies in animal models, in particular the development of gastric cancer in Mongolian gerbils infected with human isolates of H. pylori, provided conclusive evidence to the etiologic role of H. pylori in gastric cancer development (1, 43, 66, 70, 72, 115, 121, 169). The gastric histopathological changes associated with chronic H. pylori infection typically include chronic gastritis with later development of intestinal metaplasia and gastric atrophy. Most cases of gastric cancer develop on gastric mucosa with multifocal atrophic gastritis, usually with extensive intestinal metaplasia, suggesting that intestinal metaplasia and gastric atrophy are premalignant lesions of the stomach (19, 165). Further, because these lesions are intimately associated with chronic H. pylori infection, they provide an additional link of H. pylori infection with gastric carcinogenesis (Fig. 2).

Figure 2. Molecular pathways linking H.

Figure 2

Molecular pathways linking H. pylori and gastric carcinogenesis.

Mechanistically, H. pylori might cause gastric carcinomas by the converging effects of two main types of events: (i) collateral damage of inflammatory by-products causing mutational events in gastric epithelial cells and (ii) direct effects on gastric epithelial cells by H. pylori organisms or released bacterial products at different levels, including:

  • Direct toxic effects on epithelial cells
  • Alteration of the apoptosis-proliferation balance
  • Effects on transduction pathways and gene expression
  • H. pylori-induced cellular oxidative stress
  • Impairment of DNA mismatch repair
  • Alterations in cell adhesion

Although both the direct effects and complications of the inflammatory response to H. pylori are closely linked in the pathogenesis of the infection, for a more clear description we will address them separately in the sections below.

Inflammation-Related Mechanisms of H. pylori-Associated Gastric Carcinogenesis

H. pylori infection of the gastric mucosa induces an inflammatory response by the host that consists of infiltration of the mucosa by polymorphonuclear leukocytes as well as by macrophages and T and B lymphocytes. Both H. pylori and cytokines induced during infection can stimulate the recruitment and activation of inflammatory cells. When activated, inflammatory cells produce chemical mediators that include reactive oxygen species (ROS). Reactive oxygen intermediates in turn can up-regulate interleukin-8 (IL-8), further promoting the inflammatory response stimulus (143). Intermediate ROS are partly responsible for an increased oxidative stress status of gastric epithelial cells, which may be potentiated by decreased antioxidant levels associated with H. pylori infection, as reflected by lower concentrations of vitamin C in the gastric juice during H. pylori infection (23).

ROS can induce DNA damage with the accumulation of DNA mutations, contributing to the pathogenesis of gastric cancer (54). In addition, epithelial cell turnover is affected by the inflammatory response to H. pylori. This notion is supported by studies describing an increase in both epithelial cell proliferation and programmed cell death (apoptosis) in response to H. pylori infection. Apoptosis is a regulated process of cell death that is triggered by H. pylori as well as by various inflammatory mediators, including tumor necrosis factor (TNF) and interferon-gamma (IFN-γ). Exposure to H. pylori-activated peripheral blood mononuclear cells (PBMCs), but not H. pylori itself, induced Fas antigen expression in RGM-1 gastric epithelial cells, indicating a Fas-regulatory role for inflammatory cytokines in this system. When exposed to Fas ligand, RGM-1 cells treated with PBMC-conditioned medium underwent massive and rapid cell death associated with increased proliferation (69). All these changes can contribute to clonal expansion of epithelial cells that suffered mutational events and to the development of gastric cancer (25, 32, 33, 142).

Direct Toxic Effects of H. pylori on Gastric Epithelial Cells

Studies in vivo and in vitro have demonstrated a number of toxic effects of H. pylori on gastric epithelial cells that may trigger cellular apoptosis and compensatory proliferation in vivo, providing a link to the effect of direct toxicity by bacterial products and carcinogenesis (173). Exposure of human gastric epithelial cells to high concentrations of H. pylori supernatant caused lethal cell injury and increased sensitivity of AGS cells to injury by superoxide (148). H. pylori can weaken the mucous component of the gastric mucosal barrier and impair the secretory function of mucous cells. Lipase, phospholipase A2, and protease of H. pylori were shown to cause a rapid degradation of mucus glycoprotein polymer to glycopeptides, resulting in gradual loss of mucus viscosity and increased permeability of mucus to H+ (135, 147). These enzymes were also shown to inhibit mucus secretion from a mucus-secreting human cell line, resulting in decreased cytoprotection (108). Further, phospholipase A2 of H. pylori has been shown to damage epithelial cell membranes by disrupting the protective phospholipid layer at the apical surface of mucous cells (12, 106, 119, 170).

The H. pylori cytotoxin VacA induces the formation of vacuoles related to the late endosomal/lysosomal compartment in primary gastric epithelial cells in culture (59, 148). A cellular protein, VIP54, was recently described by its ability to bind H. pylori VacA (27). VIP54 is a 54-kDa protein with a cellular distribution similar to that of intermediate filaments and might be involved in interactions between intermediate filaments and late endosomal compartments (27).

H. pylori Affects the Cellular Apoptosis-Proliferation Balance

The maintenance of gastric mucosal integrity depends on the balance between cell loss due to programmed cell death (apoptosis) and cell proliferation (122, 167). In the uninfected stomach, apoptotic cells are rare and superficial, but during H. pylori infection, apoptotic cells are more numerous and located throughout the depth of gastric glands (110). The apoptotic index is higher in specimens from patients with H. pylori gastritis than in noninflamed controls, and apoptosis decreases following H. pylori eradication and resolution of gastritis (77). H. pylori strains carrying the cag pathogenicity island in general express CagA. Infection with CagA-positive strains resulted in increased gastric cell proliferation as compared to CagA-negative strains, because CagA-positive strains induced a lesser degree of apoptosis. This finding might explain the increased risk for gastric carcinoma that has been reported in some studies to be associated with infection by CagA-positive H. pylori strains (130, 149).

The precise mechanism of increased apoptosis with H. pylori infection is not known, but a number of studies have begun to provide evidence for potential mechanisms. H. pylori lipopolysaccharide (LPS) may be a virulence factor responsible for the induction of gastric epithelial cell apoptosis. LPS caused gastric mucosal responses typical of acute gastritis and marked epithelial apoptosis in rats (125). Inoculation of the H. pylori Sydney strain (SSI) in C57BL/6 mice induced caspase-3 activation followed by DNA fragmentation, which are hallmarks of apoptosis (155). Normal gastric and small bowel tissues express low levels of Fas antigen and nondetectable levels of Fas ligand. Consequent to H. pylori infection, there is elevated expression of Fas antigen in mucosal cells concurrent with the presence of Fas ligand-expressing lymphocytes. Furthermore, H. pylori stimulates apoptosis of gastric epithelial cells in vitro in association with the enhanced expression of Fas receptor (76, 132) and activation of caspase-3 (85). Additionally, H. pylori induces apoptosis in the gastric epithelium, through up-regulation of proapoptotic Bax and down-regulation of antiapoptotic Bcl-2 proteins. This phenomenon was observed in H. pylori-infected patients with duodenal ulcer and in Kato III gastric cancer cells, indicating a direct apoptotic effect of H. pylori on mucosal cells (89). Recent studies in the Mongolian gerbil model of H. pylori infection have shown that in H. pylori-infected gerbils antral apoptosis is seen early during infection and is followed later by increased cell proliferation (123), which correlates well with human studies (75).

An antiproliferative activity of H. pylori was shown to affect the proliferation of various mammalian cell lines (U937, Jurkat, AGS, Kato III, HEP-2, and P388D1), and this effect was associated with diminished protein synthesis. The responsible H. pylori factor might be a protein of 100 kDa (PIP, for proliferation-inhibiting protein) (87, 149). Ammonia, which is a cytotoxic factor generated by H. pylori, is involved in gastric mucosal injury and inhibited the proliferation of HGC-27 cells in a dose-dependent manner. Flow-cytometric analysis showed S-phase accumulation of HGC-27 cells, suggesting that ammonia inhibits the growth of gastric cells in S phase. This mechanism could make a significant contribution to the pathogenesis of H. pylori-associated gastric mucosal atrophy, a known risk factor of gastric cancer (105).

In summary, H. pylori bacterial products as well as inflammation-related products have been shown to perturb cell proliferation and increase apoptosis in gastric epithelial cells. In vivo, these effects result in increased cellular turnover and compensatory proliferation of surviving epithelial cells (38, 122, 138). Accordingly, H. pylori eradication results in decreased cell proliferation and apoptosis (68). The increased cell turnover resulting from H. pylori infection literally exposes the epithelium to a greater risk of expansion of cells that have incurred mutations, in this manner promoting cancer development.

H. pylori Causes Imbalance of Transduction Pathways and Affects Gene Transcription in Gastric Epithelial Cells

Attachment of H. pylori to gastric cells results in pedestal formation and cytoskeleton rearrangement similar to that described for enteropathogenic Escherichia coli. H. pylori cell adherence was shown to induce tyrosine phosphorylation of two proteins of 145 and 105 kDa in gastric epithelial cells (139, 140). There is now evidence that the 145-kDa protein corresponds to H. pylori CagA (3, 152). CagA-positive H. pylori strains translocate the bacterial protein CagA into gastric epithelial cells by a type IV secretion system, encoded by the cag pathogenicity island. CagA is tyrosine phosphorylated and induces changes in the tyrosine phosphorylated state of distinct cellular proteins (118).

H. pylori infection is associated with the induction of several cytokines, including IL-8 (25, 105, 175). NF-κB regulates a variety of genes involved in cell growth and immune response and is a transcriptional regulator of IL-8 production. NF-κB activation after bacterial infection may be an important defense mechanism or part of the response of gastrointestinal epithelial cells to infection. Infection with H. pylori was shown to activate NF-κB directly in gastric epithelial cells in vitro and in vivo and to induce nuclear translocation of both NF-κB p50/p65 heterodimers and p50 homodimers. Nuclear translocation of NF-κB is followed by increased IL-8 mRNA and protein levels, consistent with NF-κB up-regulation of IL-8 gene transcription (81). Activation of IL-8 through NF-κB appears to occur through a sphingomyelinceramide pathway (104). Infection of AGS cells with an H. pylori Cag-positive strain rapidly induced a dose-dependent activation of extracellular signal-regulated kinases (ERK), p38, and c-Jun N-terminal kinase (JNK) MAP kinases (82).

Another study showed that exposure of gastric epithelial cells to H. pylori induces activation of the transcription factors c-fos, c-jun, and AP-1. This effect appears to occur through activation of the ERK/MAP kinase cascade, resulting in Elk-1 phosphorylation and increased c-fos transcription (107). Since MAP kinases regulate cell proliferation, differentiation programmed death, stress, and inflammatory responses, activation of gastric epithelial cell MAP kinases by H. pylori may play a role in inducing gastroduodenal inflammation and carcinoma (82). H. pylori infection can alter the expression of many other epithelial cell genes. Increased expression of amphiregulin and heparin-binding epidermal growth factor-like growth has been shown to be mediated by an H. pylori factor greater than 12 kDa in size (131). The availability of high-throughput screening using microarray gene expression analysis is expected to provide an abundance of information at a fast pace.

H. pylori Infection, Oxidative Stress, and the Accumulation of Genetic Mutations

Oxidative injury has been implicated in various diseases associated with chronic inflammation, such as H. pylori infection. Apoptosis and oxidative stress are closely interrelated and may play a determinant role in the evolution of chronic gastritis to gastric carcinogenesis. Exposure of gastric epithelial cells to H. pylori resulted in the generation of ROS (116). Moreover, addition of either TNF-α or IFN-γ for 24 h resulted in enhanced ROS production in response to bacteria or H2O2. DNA 8-hydroxydeoxyguanosine (80HdG) is a sensitive marker for oxidative DNA damage. Concentrations of 8HdG were detected at significantly higher frequency in chronic atrophic gastritis, in the presence of severe disease activity, intestinal metaplasia, and H. pylori infection (39). After eradication of H. pylori, 80HdG contents were significantly decreased (55). Patients infected with H. pylori expressed more inducible nitric oxide synthase (iNOS), and higher levels of iNOS were caused by infection with CagA-positive H. pylori strains (101). Increased levels of iNOS and cyclooxygenase (COX-2) were demonstrated in H. pylori-associated gastritis (44). Both nitric oxide and COX-2 products have been shown to have mutagenic potential, possibly linking these molecular alterations seen with chronic gastritis with increased risk of gastric carcinoma development (54, 126).

Although many studies using surrogate markers for biological mutations have been done, much less is known about the specific gene mutations that occur critically in the early stages of gastric carcinogenesis. Mutation of the TP53 gene has been described in a small number of cases of premalignant gastric mucosa with intestinal metaplasia (73, 141). K-ras mutations were found in 14.4% of all baseline biopsies from atrophic gastritis patients, and an association was found between the presence of K-ras mutations in baseline biopsies and the progression of preneoplastic lesions. Among those patients with atrophic gastritis without metaplasia, 19.4% (6 of 25) contained K-ras mutations, suggesting that mutation of this gene is an early event in the etiology of gastric carcinoma (49).

H. pylori-Associated Impairment in DNA Mismatch Repair

Mutation surveillance and repair are carried out by the DNA repair system. DNA mismatch repair (MMR) corrects mutations that occur during cell replication (88). With increased cell turnover of the gastric mucosa during active H. pylori infection, an increased load of mutations may occur as a consequence of the infection and other environmental risk factors. Under these conditions, a situation where DNA repair might be overwhelmed may develop. Microsatellite instability (MSI) is a marker of mutations that develop subsequent to deficient DNA MMR activity. The DNA MMR genes hMSH3 and hMSH6 and growth factor receptors and transforming growth factor β-RII are frequently mutated in MSI-positive gastric cancers (16, 111, 174). The expression of the MMR genes hMLH1 and rarely hMSH2 is usually abolished in MSI-positive gastric cancers (41, 56, 99).

MSI can result in mutations in the coding regions of other critical genes involved in regulation of cellular proliferation and differentiation. Recent studies found that patients with MSI-positive tumors showed a significantly higher frequency of previous H. pylori infection (171), and patients with MSI-positive tumors were more likely to have active H. pylori infection (100). Using a coculture in vitro system, gastric cancer cell lines exposed to H. pylori showed decreased levels of both MutS (hMSH2 and hMSH6) and MutL (hMLH1, hPMS2, and hPMS1) DNA MMR proteins (84). Additionally, H. pylori caused MSI in longer-term cocultures. These data suggest that deficient MMR caused by H. pylori underlies MSI in the gastric epithelium, providing a mechanism of mutation accumulation in the gastric mucosa during early stages of H. pylori-associated gastric carcinogenesis.

H. pylori-Associated Changes in Epithelial Adhesion Molecules

Proteins involved in epithelial adhesion are essential for maintenance of tissue structure and have a prognostic importance in gastric cancer. E-cadherin is essential for maintaining cell adhesion, as well as for differentiation, and it is thought to act as a suppressor of epithelial tumor cell invasiveness and metastasis. A study by Terres et al. reported that H. pylori infection was significantly associated with down-regulation of E-cadherin (158). However, Blok et al. found no significant differences in E-cadherin expression between H. pylori-positive and H. pylori-negative early gastric carcinoma patients (15).

Development of Gastric Cancer in H. pylori-infected Animals

Gastric carcinogenesis is multifactorial and some environmental factors are believed to be involved in this process (19), including excessive intake of salt (21), N-nitroso compounds in foods, and low consumption of fresh fruits and vegetables. H. pylori has been shown to be associated with an increased risk of both intestinal type and diffuse type gastric cancers (97), which correspond, respectively, with well-differentiated and poorly differentiated types in the Japanese classification (6, 34, 57, 70, 97, 115, 121).

Recently, evidence that H. pylori infection may induce gastric adenocarcinomas in animal models has accumulated (62, 67, 145, 153, 159, 169). Mongolian gerbils with long-term infection with H. pylori developed gastric cancer, with treatment with low-dose chemical carcinogens, N-methyl-N-nitrosourea (MNU) or MNNG, or without them. The Mongolian gerbil model resembles the human situation in its susceptibility and response to H. pylori infection (63), since the bacterium can induce chronic active gastritis, gastric ulceration, and duodenal ulceration. Therefore, the Mongolian gerbil model has an advantage for investigating gastric carcinogenesis developed as a result of H. pylori infection in humans. In this section the development of gastric cancer in Mongolian gerbil models with H. pylori infection and the relevance of this animal model will be discussed.

Development of Animal Models of H. pylori Infection

The IARC/WHO conclusions were based predominantly on several epidemiologic studies in humans. To generate direct evidence of the causal relationship between H. pylori infection and occurrence of gastric cancer, we need to conduct clinical intervention studies in which eradication of H. pylori can reduce the occurrence of gastric cancer in humans. Alternatively, we can observe the development of gastric cancer in animal models of H. pylori infection.

In the first decade after the discovery of this organism, an inoculation of H. pylori was reported to induce gastritis in beagle dogs, Japanese monkeys, miniature gnotobiotic pigs, mice, and Mongolian gerbils (63, 79, 80, 90, 128, 146, 168). These animal models indicated that H. pylori infection could induce histologic gastritis, which was characterized by numerous infiltrations of inflammatory cells, epithelial erosion, and degeneration. Fujioka et al. infected Japanese monkeys with H. pylori and then followed the animals for a prolonged period, detecting the occurrence of gastric mucosal atrophy 1.5 years after inoculation (45). However, these animals are too big to use for cancer experiments, and there are still no reports on the development of gastric cancer in these animal models.

Although a mouse model resembling human H. pylori chronic gastritis is available, a specialized H. pylori strain, SS1, or Helicobacter felis was used, with gastric carcinoma not being detected (98). Hirayama et al. (63) reported first in 1996 that H. pylori could induce gastritis, gastric ulceration, and intestinal metaplasia during long-term infection in Mongolian gerbils models. In this model, H. pylori could colonize the stomach and induce gastritis 12 weeks after inoculation and induce gastric ulceration at 24 weeks and intestinal metaplasia at 24 to 48 weeks. These histologic characteristics, infiltration of numerous neutrophils and lymphocytes, with defects in the gastric mucosal tissue reaching the muscular layer, and occurrence of intestinal metaplasia resembled that of human H. pylori infection. After this report, Mongolian gerbil models began to be used in experiments in the study of gastric carcinogenesis by H. pylori infection in Japan.

In 1998, three papers on the development of gastric cancer using Mongolian gerbil models were published from Japan and provided experimental data supporting the role of H. pylori infection in the occurrence of gastric cancer. Sugiyama et al. (153) first demonstrated that H. pylori could increase the incidence of MNU-induced gastric cancer in the Mongolian gerbil animal model. A total of 170 male Mongolian gerbils were used in the study. Seven of 19 Mongolian gerbils (36.8%), which were inoculated with the ATCC 43504 type strain of H. pylori first and then treated with 10 ppm of MNU for 20 weeks, developed gastric adenocarcinoma 40 weeks after the study commenced. Five of seven cancers (71.4%) were signet ring-cell carcinomas, one was a poorly differentiated adenocarcinoma, and one was a well-differentiated adenocarcinoma. In cases of treatment with 30 ppm of MNU for 6 weeks first and then inoculation of H. pylori, 6 of 18 Mongolian gerbils (33.3%) developed gastric adenocarcinomas at 40 weeks. Four of six cancers (66.6%) were well-differentiated adenocarcinomas, one was signet ring-cell carcinoma, and one was poorly differentiated adenocarcinoma. These observations may suggest that the time of inoculation of H. pylori, the dose of chemical carcinogens, and the order of inoculation of H. pylori and administration of chemical carcinogens are critical to determine the histological types of gastric cancers. This hypothesis, however, has not been confirmed in all studies using the Mongolian gerbil model (144). In one study, 20 Mongolian gerbils infected with H. pylori ATCC 43504 alone, 18 Mongolian gerbils treated with 10 ppm of MNU alone for 20 weeks, or 18 Mongolian gerbils treated with 30 ppm of MNU alone for 6 weeks did not develop gastric cancer at all. These findings suggest that while H. pylori may induce gastric cancer in Mongolian gerbils, infection plus administration of very low-dose chemical carcinogens may be needed.

In contrast, Watanabe et al. (169) reported that long-term infection with H. pylori alone could induce gastric adenocarcinoma in the Mongolian gerbil model 62 weeks after inoculation. They demonstrated that 10 of 27 H. pylori-infected Mongolian gerbils (37%) developed gastric cancers, all of which were well-differentiated, intestinal type carcinomas. Interestingly, the investigators used an H. pylori strain (TN2GF4) that was originally isolated from a patient with gastric ulcer and then passaged in the stomach of Mongolian gerbils several times before resolution. This strain had vacuolating cytotoxin and cagA genes and appeared extremely spiral in form. A key point was that gastric cancer was not observed in the infected animals 39 weeks or 52 weeks after inoculation with H. pylori. Honda et al. (67) also reported in the same year that two of five Mongolian gerbils (40%) infected with H. pylori ATCC 43504, also containing the vacuolating cytotoxin and cagA genes, developed gastric cancer 72 weeks after inoculation that was well-differentiated adenocarcinoma. However, Hirayama et al. (62) reported that only one gastric cancer developed in Mongolian gerbils infected with H. pylori ATCC 43504 at 96 weeks of follow-up (1.8%) and the pathology was a poorly differentiated adenocarcinoma.

In 1999, Shimizu et al. (145) reported that H. pylori infection plus administration of MNNG, a different chemical carcinogen, enhanced the development of gastric cancer at 50 weeks, compared to administration of MNNG alone or H. pylori infection alone. As MNNG itself has anti-H. pylori effect, high-dose administration of MNNG eradicated H. pylori in the animals. Six of 25 Mongolian gerbils (24%), which were administered 60 mg of MNNG first for 10 weeks followed by H. pylori inoculation, developed gastric cancer. Of the six cancers, three were well-differentiated adenocarcinomas, one was poorly differentiated adenocarcinoma, and two were signet ring-cell carcinomas. In contrast, there was no cancer in animals administered MNNG alone. Of 25 Mongolian gerbils that were infected with H. pylori first and then administered 20 mg of MNNG for 30 weeks, 15 animals (60%) developed gastric cancer at 50 weeks. Nine of these cancer were well-differentiated adenocarcinomas, two were poorly differentiated adenocarcinomas, and four were signet ring-cell carcinomas. In their report they noted that the titers of anti-H. pylori antibodies in the cancer-bearing Mongolian gerbils were higher than in cancer-free Mongolian gerbils treated in the same manner. These findings may suggest that host immune response has some linkage to tumor development in these models (10, 28, 37).

Tokieda et al. (159) demonstrated that H. pylori infection plus administration of MNNG increased the incidence of gastric cancer, compared to administration of MNNG alone. Four of six Mongolian gerbils (66.7%) with H. pylori infection followed by MNNG for 20 weeks developed gastric cancer 52 weeks after inoculation. The incidence was higher than in Mongolian gerbils administered the same dose of MNNG alone (17.6%).

These six studies were conducted under different experimental conditions, being (i) cotreatment with chemical carcinogens, (ii) use of different strains, and (iii) different observation periods. As the result of these differences, the incidence of gastric cancer and the subtype of gastric cancer might have been influenced (Table 2). The most troublesome issue is the diagnostic criteria for gastric cancer in Mongolian gerbils. In general, gastric cancer in humans is diagnosed by three histological characteristics, (i) cellular and nuclear atypia, (ii) aberrant glandular structure, and (iii) invasion (137). H. pylori-infected Mongolian gerbils sometimes exhibit invasive glands into muscular layer and aberrant glands, with these histological changes being reversed upon H. pylori eradication. These histological characteristics in this model can be confused with well-differentiated adenocarcinomas developed in experiments in which animals are infected with H. pylori alone. On the other hand, treatment with low-dose chemical carcinogens sometimes induces cellular and nuclear atypia. Therefore, a diagnosis of well-differentiated adenocarcinoma in Mongolian gerbils induced by H. pylori infection needs to be prudent.

Table 2. Development of gastric cancer in H. pylori-infected Mongolian gerbils.

Table 2

Development of gastric cancer in H. pylori-infected Mongolian gerbils.

In terms of these criticisms, the incidence of well-differentiated adenocarcinomas in experimental models, either infected with H. pylori alone or with coadministration of low-dose chemical carcinogens, may be overestimated. To resolve these issues, common criteria for diagnosis of gastric cancer in Mongolian gerbils are required or histology needs to be supported by genetic evidence to confirm the diagnosis of gastric cancer.

In relation to cancer prevention, Shimizu et al. (145) reported that H. pylori eradication could decrease the incidence of gastric carcinomas in Mongolian gerbils induced by H. pylori inoculation plus administration of low-dose chemical carcinogens. Of 23 Mongolian gerbils administered MNU in the drinking water at 30 ppm for a total of 5 weeks and followed by infection with H. pylori, 15 animals developed gastric cancer at 50 weeks (65.2%). The other 24 Mongolian gerbils administered MNU and later infected with H. pylori were given treatment to cure the infection at 21 weeks. At week 50, the prevalence of gastric cancer in H. pylori-eradicated Mongolian gerbils was significantly lower (20.8%) than in H. pylori-infected Mongolian gerbils. These observations indicate that eradication of H. pylori in the early phase of the process reduced the occurrence of gastric cancer in this model. This result suggests that H. pylori eradication treatment may be an effective approach in terms of gastric cancer prevention in humans.

Genetic Alterations in Gastric Carcinogenesis

Gastric carcinogenesis in humans is a multistep process as well as multifactorial. An accumulation of genetic alterations may result in development of gastric cancer, having an analogy with that of colon cancer (166). Genetic alterations occur in oncogenes, tumor suppressor genes, cell adhesion molecules, telomere and telomerase activity (95), and genetic instability (16, 171). Different histological types of gastric cancer exhibit different patterns of genetic alterations. Tahara (156) clearly summarized the genetic alterations in well-differentiated intestinal type and poorly differentiated diffuse type gastric adenocarcinomas (Table 3). The p53 mutation in tumor suppressor genes, cyclin E and p21 overexpression in cyclin and CDK inhibitors, transforming growth factor α overexpression (157) in growth factors, and CD44 aberrant transcript (176) in cell adhesion molecules are relatively observed in both types of gastric cancers. In contrast, antigen-presenting cell mutation (112) and erbB-2 amplification (61) are likely to occur in well-differentiated gastric cancers, and K-sam amplification and mutation or loss of E-cadherin occurs in poorly differentiated gastric cancers (31, 60). Since specific carcinogens have specific mutagenic properties, the types of genetic mutations present in a specific form of gastric cancer may provide important clues to the mutagenic agent.

Table 3. Genetic alterations in both types of human gastric cancera.

Table 3

Genetic alterations in both types of human gastric cancera.

The p53 is a nuclear protein and functions as guardian of the genome (96). The wild-type p53 binds to the responsive element on DNA and induces WAF1/CIP1/p21, which binds to cyclin-dependent kinase and induces G1 arrests (58). Another major function is to induce apoptosis via induction of Bax, Fas/Apo-1, and the other apoptosis-related proteins (13, 127). Therefore, the mutant p53 might link to the dysregulation of a cell cycle and apoptosis. In fact, p53 mutation is the most widely described molecular alteration in human cancers (65, 74, 78). The mutation occurs in 40 to 70% of diffuse or intestinal types of human gastric cancers. Shiao et al. (141) described that p53 mutated in 58% with dysplasia and 67% with carcinoma of the stomach. Ochiai et al. (117) reported that 4 of 10 incomplete type intestinal metaplasias demonstrated p53 mutation on exon 5 or exon 7 by PCR-single strand conformation polymorphism analysis and direct sequencing. Therefore, p53 mutation might occur in the early steps of gastric carcinogenesis. As described above, the Mongolian gerbils may be the best animal model to investigate the gastric carcinogenesis induced by H. pylori infection, since this model resembles human pathology associated with H. pylori infection, that is, chronic active gastritis, gastric atrophy, intestinal metaplasia, and gastric carcinoma. However, because this animal has not been popular in cancer experiments to date, unfortunately, the genetic data linked to oncogenesis are lacking. In addition, specific antibodies for use in Mongolian gerbils are also lacking. These are some of the disadvantages of the Mongolian gerbil model for the study of gastric cancer. To break through this bottleneck, we need the genetic information associated with oncogenesis in Mongolian gerbils, such as the p53 gene, which might be an appropriate gene to investigate the oncogenic mechanisms of both types of gastric cancer induced by H. pylori infection.


Gastric cancer is an example of a cancer associated with a chronic inflammatory process that results in a metaplastic epithelium and cancer (51). Other examples are Barrett's esophagus, squamous metaplasia in the bronchus in smokers, chronic inflammation in ulcerative colitis, or bladders infected with schistosomes. In general, the risk is related to the extent and severity of the atrophic changes present. All of the problems listed by Evans and Mueller regarding making causal associations between viruses and cancer (35) are applicable to H. pylori and gastric cancer, including (i) there is a long incubation or induction between infection and cancer, (ii) the candidate agent is common and the cancer is relatively rare, (iii) the need for cofactors, (iv) the cause of cancer may vary depending on geographic areas or age, (v) different strains may have different oncogenic potential, (vi) the human host plays a critical role in susceptibility (age at infection, genetic characteristics, status of immune system), (vii) cancer is multifactorial and the agent may play roles at different points, and (viii) there are often other causes of the cancer.

Differences in the incidence of gastric cancer in populations with a similar high prevalence of H. pylori infection can be related to the differences in the age of acquisition of chronic atrophic gastritis (Fig. 3), which, in turn, is related to an interaction between environmental factors, especially diet, and H. pylori infection. The incidence of gastric cancer varies in different regions and can fall rapidly, even in the same population in relation to levels of sanitation, standards of living, food storage and the use of salt, changes in diet with fresh fruits and vegetables being always available, and a fall in the incidence of febrile childhood diseases (50). Progression from superficial to atrophic gastritis (and subsequently gastric cancer) is facilitated by irritants such as salt, carbohydrates, and abrasive dusts and retarded by fresh fruits and vegetables (21, 22). Because H. pylori infection causes the underlying gastritis, it is the critical variable. Histologic studies have shown that gastric cancer without underlying gastritis is rare (51). Elimination of H. pylori will make gastric cancer a rare disease. We look forward to that day.

Figure 3. Status of the gastric mucosa in two populations with a high incidence of H.

Figure 3

Status of the gastric mucosa in two populations with a high incidence of H. pylori infection. One population (A) experiences a rapid transition of superficial gastritis to atrophic pangastritis. Gastric cancer begins to be seen in patients in their 40s, (more...)


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Copyright © 2001, ASM Press.
Bookshelf ID: NBK2445PMID: 21290744


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