Search

The relation between Helicobacter pylori (Hp) eradication and prevention of stomach carcinoid development has hitherto remained unclear. We therefore examined this problem using an Hp-infected and Hp-eradicated Mongolian gerbil (MG) model. Enterochromaffin-like (ECL) lesions (hyperplasia/dysplasia and carcinoid) were histopathologically evaluated in the glandular stomachs of Hp-infected and Hp-eradicated MGs. In addition, serum gastrin levels were analyzed. Hp infection induced significant increase in the development of ECL lesions in the glandular stomach, as well as serum gastrin levels as compared with non-infected MGs, while Hp eradication was associated with significant alleviation. The development of ECL lesions in the glandular stomach strongly correlated with titers of anti-Hp antibodies and serum gastrin levels in MGs. In conclusion, Hp infection induces carcinoid development, and Hp eradication prevents its occurrence in the glandular MG stomach, this being strongly linked with reduction in serum gastrin levels.

Aims: We have previously demonstrated the importance of gastric and intestinal phenotypic expression for the histogenesis of stomach cancer. However, the phenotypes of stomach cancers arising after Helicobacter pylori (Hp) eradication have hitherto remained unclear. We therefore examined a series of lesions occurring after Hp eradication in the Mongolian gerbil (MG) model., Methods: Totals of 6 and 20 advanced glandular stomach cancers were evaluated in Hp-eradicated and Hp-infected MGs treated with N-methyl-N-nitrosourea (MNU-MGs), using several gastrointestinal epithelial phenotypic markers. The lesions were divided phenotypically into gastric (G type), gastric-and-intestinal mixed (GI type), intestinal (I type), and null (N type) phenotypes., Results: All 4 differentiated type lesions in Hp-eradicated MNU-MGs were classified as G type, while both of the undifferentiated lesions exhibit the GI type. In Hp-infected MNU-MGs, the lesions were classified as 10 G, 8 GI, and 2 I types, with undifferentiated type lesions having more intestinal phenotypic expression than their differentiated counterparts (P< 0.01)., Conclusions: Our data suggest that the differentiated stomach cancers exhibit the G type in Hp-eradicated MNU-MGs, suggesting that a kind of non-neoplastic G type gland may be precancerous. Intestinalization may still occur, especially in undifferentiated stomach cancers, even if Hp eradication is successful.

Helicobacter pylori (H. pylori) infection causes chronic gastritis and is also related to gastric carcinoma. The present study focused on severity of H. pylori-induced gastritis as a determinant of carcinogenesis. Seven-week-old male Mongolian gerbils were inoculated with H. pylori at experimental weeks 0, 12, or 18, then given N-methyl-N-nitorosourea (MNU) from weeks 20-40. At week 70, stomachs were then excised for histological examination 70, 58, or 52 weeks after H. pylori inoculation, respectively (Groups A, B, and C for long-, middle-, and short-term). The respective incidences of glandular stomach adenocarcinomas were 65.0% (13/20), 20.0% (2/10), and 23.0% (3/13) (P<0.05). Higher scores of infiltration of inflammatory cells, hyperplasia, intestinal metaplasia and mucosal bromodeoxyuridine (BrdU) labeling index in antrum and corpus mucosa, were seen in group A than B or C (P<0.05) and serum anti-H. pylori IgG titer and gastrin levels were also significantly higher, along with mRNA levels for mucosal interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). The results demonstrated the term and severity of H. pylori infection to play important roles in gastric carcinogenesis, with essential involvement of chronic inflammation, especially increased rates of cell proliferation, in H. pylori-associated carcinogenesis.

Diagnosis and treatment of gastric cancer has now been established, and prevention is thought to be of importance to overcome this disease. Many experimental and clinical researches have clarified the pivotal role of H. pylori infection in gastric carcinogenesis. Therefore, prevention of gastric carcinogenesis by H. pylori eradication seems to be promising, and the possibility has been suggested by experimental and clinical studies. The issues to be solved are to select the candidates for eradication and to assess the timing of eradication. Development of new diagnostic methods and biomarkers for H. pylori eradication is required.

A 71-year-old man with a Helicobacter pylori infection-negative and API2-MALT1 translocation-negative extranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type of the stomach has been followed conservatively for over 5 years. The lesion has shown no major morphological changes or malignant progression into a diffuse large-cell type during the time course. The absence of genetic translocation of API2-MALT1 was confirmed with fluorescence in situ hybridization (FISH). The prognosis of H. pylori-negative and API2-MALT1 translocation-negative low-grade MALT lymphoma is unknown, and a standard treatment for such lymphoma has yet to be defined. The case of MALT lymphoma negative for both of the above factors that we report has shown no obvious rapid progression or malignant change over the long-term course. Although curative operation and/or chemoradiotherapy should still be discussed as the treatment of choice, the treatment of this type of lymphoma must be carefully determined on a case-by-case basis, according to its biological status and prognosis.

In the present study, we aimed to establish an additional standardized protocol with a higher H. pylori eradication rate in the remnant stomach. Fifty-five H. pylori-positive patients were randomly allocated to one of three regimens: LAC--lansoprazole, amoxicillin, and clarithromycin b.i.d. for 7 days (n = 17); LAC+CET--LAC b.i.d. plus cetraxate q.i.d. for 7 days (n = 20); and LEFT--LAC for 7 days in a horizontal body position on the left side for 30 min (n = 18). Patient compliance and side effects were checked via interviews. H. pylori eradication was successful in 75, 72, and 41% in LAC+CET, LEFT, and LAC, respectively. The eradication rate was significantly higher in LAC+CET than in LAC (P = 0.024) but not in LEFT (P = 0.058). Adverse events that occurred in each group were almost all mild ones. Cetraxate plus LAC for 1 week is a safe and effective regime for the eradication of H. pylori in patients after partial gastrectomy.

Mongolian gerbils are an ideal animal model to explore the role of H. pylori on cancer development. However, there have been no established adenocarcinoma cell lines from this model animal. In the present study, we have established cancer cell lines from a primary gastric cancer tissue of a Mongolian gerbil. The derived cells could be stably attached with H. pylori, revealed under a scanning electron microscope, and easily transplanted to the nude mice. Rapid phosphorylation of IkappaB, Erk1/2, and AKT of these cells was observed by Interleukin-1 beta stimulation, and luciferase reporter gene assay on transcriptional activation of Nuclear Factor kappa B after challenging with either H. pylori NCTC11637 or its isogenic cagE-knockout mutant, H. pylori revealed the cagE-dependent NF-kappaB transcriptional activation. The newly established cancer cell lines from the in vivo gastric carcinogenesis model animal, the Mongolian gerbil, can be used to develop effective therapeutic strategies against gastric cancer, especially in exploring the effect of H. pylori, and thus might greatly contribute to gastric cancer prevention and treatment in humans.

Mongolian gerbils infected with Helicobacter pylori (H. pylori ) develop heterotopic proliferative glands (HPGs) in the glandular stomach submucosa. To investigate the effects of H. pylori eradication on cell turnover in HPGs, three antibiotics, lansoprazole, amoxicillin and clarithromycin, were administered at 50 or 75 weeks after inoculation of H. pylori, and the stomachs were excised for histological examination at 1, 2, 4, 8 or 25 weeks thereafter. The HPGs were classified into gastric type (G-type) and others (GI + I-type), which included both pure intestinal (I-type) and gastric-and-intestinal mixed type (GI-type). Apoptosis and cell proliferation were evaluated by means of TUNEL assay and BrdU labeling, respectively. At 8 weeks post-eradication, apoptotic indices were significantly increased in the eradication group (G-type: 2.5%; GI + I-type: 7.2%) compared to the non-eradication group (G-type: 0.6%; GI + I-type: 2.1%: P < 0.01), while BrdU labeling indices were significantly decreased (G-type: 1.9%; GI + I-type: 6.8% as compared with 4.3% and 13.2%, respectively, P < 0.01 for both). At 25 weeks, the apoptotic indices were similarly higher [G-type: 0.4 (eradication group) vs. 0.2% (non-eradication group); GI + I-type: 5.8 vs. 1.1%, both P < 0.01], and the BrdU labeling indices (G-type: 0.8 vs. 2.2%, P < 0.01; GI + I-type: 5.1 vs. 11%, P < 0.05) continued to be lower in HPGs. Furthermore, there were highly significant reductions in the areas of HPGs at 8 and 25 weeks post-eradication. These findings demonstrated that eradication results in apoptosis and reduction of proliferation of HPGs in H. pylori-infected gerbils, these lesions thus being apparently reversible through regulation of cell kinetics.

The goal of this study was to elucidate whether beta-catenin gene mutations might contribute to glandular stomach carcinogenesis in Helicobacter pylori (H.pylori)-infected Mongolian gerbils. Firstly, exon 3 of gerbil beta-catenin cDNA, a mutation hot spot, was cloned and sequenced and found to have 89.3% homology with the human form and 95.5% with the rat and mouse forms. Peptide sequence in this region was shown to be 100% conserved in these mammals. Then, 45 stomach adenocarcinomas induced with N-methyl-N-nitrosourea (MNU) plus H. pylori infection and 7 induced with MNU alone were examined for beta-catenin expression by immunohistochemistry and for DNA mutations using a combination of microdissection and PCR-single strand conformation polymorphism analysis. One gastric cancer in the MNU + H. pylori group (2.2%) displayed nuclear (N) beta-catenin localization, 3 (6.7%) showed cytoplasmic (C) distribution in local regions, and 41 (91.1%) demonstrated cell membrane (M) localization. Tumors induced by MNU alone showed only membranous beta-catenin localization (7/7). Analysis of exon 3 of the beta-catenin gene dem-onstrated all tumors with membrane or cytoplasmic staining as well as surrounding normal mucosa (S) to feature wild-type beta-catenin. In contrast, the lesion with nuclear staining had a missense mutation at codon 34 [GAC (Gly) --> GAA (Glu)] in exon 3 (1/1 = 100%, N vs. M, P < 0.05; and N vs. S, P < 0.05). In conclusion, these results suggest that beta-catenin may not be a frequent target for mutation in stomach carcinogenesis in MNU + H. pylori-treated gerbils.

Helicobacter pylori (Hp) infection and gastric carcinogenesis are known to have a close relationship, but the effect of eradication of Hp on Hp-related gastric carcinogenesis has not been fully studied experimentally. To evaluate the effect of eradication in gastric carcinogenesis, an experimental model with eradication in the early, middle or late period was studied using Hp-infected and N-methyl-N-nitrosourea (MNU)-treated Mongolian gerbils. The animals were divided into seven groups: group A (MNU + Hp + eradication at 15 w), group B (MNU + Hp + eradication at 35 w), group C (MNU + Hp + eradication at 55 w), group D (MNU + Hp), group E (MNU), group F (Hp) and group G (control). The tumor incidences at week 75 in the early (group A), middle (group B) and late (group C) eradicated groups were 6.7%, 27.3% and 38.2%, respectively. The incidence of 56.3% in the non-eradicated group was the highest (group D). Incidences in group E, group F and group G were 6.3%, 0.0% and 0.0%, respectively. The tumor incidences were related to the period of inflammatory status induced by Hp infection. Hp infection strongly enhanced gastric carcinogenesis initiated with a chemical carcinogen, and following eradication at an early period this enhancing effect was effectively reduced. Eradication at an early stage of inflammation might be effective in preventing Hp-related gastric carcinogenesis.

The effects of helicobacter pylori infection on gastric disorders have been proven by many epidemiological and experimental studies. To explore the relationships between h. Pylori infection and gastric carcinogenesis, many factors, including host responses, environmental status, and the virulence factors of the bacteria should be taken into account. Mongolian gerbils ( meriones unguiculatus) can be easily infected with h. Pylori, and provide an excellent in-vivo experimental model to clarify the role of h. Pylori in active gastritis, peptic ulcers, intestinal metaplasia, and gastric carcinoma. Studies have revealed that h. Pylori infection markedly enhances all histological types of gastric cancers in gerbils treated with a chemical carcinogen. Eradication reduced the enhancing effect of h. Pylori on gastric carcinogenesis, whereas a high-salt diet synergistically enhanced the effect of h. Pylori. Various factors involving inflammation, cell proliferation, and cell differentiation could be examined with this experimental model to help elucidate this mechanisms of gastric carcinogenesis.

Helicobacter pylori(Hp) infection and a high salt diet are considered important enhancing factors in gastric carcinogenesis. A high salt diet is considered to cause temporary tissue damage, alteration of the viscosity of the protective mucous barrier, and to facilitate colonization of Hp, resulting in gastric tumor progression. The high prevalence of Hp infection and high salt diets might have greatly affected the rates of gastric carcinogenesis, especially in Japan. In Mongolian gerbils treated with a chemical carcinogen, the highest incidence of adenocarcinoma was observed in animals with both a high salt diet and Hp infection. The two factors of Hp infection and a high salt might interact to produce gastric cancers, and thus have implications for cancer prevention.

Helicobacter pylori is known to infect a half of the world's population and has been closely linked to an increased risk of the development of gastric adenocarcinoma, making it a pathogen of potentially great significance. The IARC/WHO in 1994 designated H. pylori a class I carcinogen based on epidemiological evidence. A direct association between H. pylori infection and the induction of gastric carcinoma has been recently demonstrated in a Mongolian gerbil model with use of chemical carcinogens, giving further credence to the role of this organism as a promoter in gastric carcinogenesis. However, the exact mechanisms underlying the link between H. pylori infection and gastric carcinogenesis still remain to be elucidated. To approach this issue, it is necessary to find environmental factors and to clarify genetic events during carcinogenesis in in vivo models.

Helicobacter pylori (H. pylori) is now well known to be associated with stomach cancer, with infection during childhood rather than as an adult considered to be more important for carcinogenesis. To evaluate the difference in susceptibility to stomach carcinogenesis in relation to age of acquisition of H. pylori infection, we designed an experiment involving inoculation of H. pylori ATCC43504 followed by N-methyl-N-nitrosourea (MNU) treatment at different ages. Four-week-old male Mongolian gerbils (MGs) were divided into twelve groups. H. pylori was inoculated at 4, 18 and 32 weeks of age, as representatives of early, middle and late infection, respectively. Two weeks later, the animals were treated with MNU. Groups without H. pylori and/or MNU were included as controls. The incidences of adenocarcinomas at 52 weeks after the inoculation in the early (H. pylori+MNU), middle (H. pylori+MNU), and late (H. pylori+MNU) group were 60% (12/20), 18.4% (2/11), and 10% (2/20), respectively. The corresponding figures were 14.8% (4/27), 0% (0/11), and 0% (0/21) in the MNU-alone groups. A higher titer of serum IgG for H. pylori and higher gastrin level were seen in the early-infected compared to the middle and the late groups (P<0.01). The results clearly demonstrated that early acquisition of H. pylori significantly increases gastric chemical carcinogenesis with MNU, as compared to the case with later infection, possibly because of differences in host gastric mucosal factors and immunologic responses.

Helicobacter pylori (Hp) infection and high-salt diet administration are both considered to be important factors in gastric carcinogenesis in man. To investigate the interaction of these two factors on gastric carcinogenesis, an experimental study of the carcinogenesis model was performed. Mongolian gerbils were treated with 20 ppm of N-methyl-N-nitrosourea (MNU) in their drinking water for alternate weeks for a total of 5 weeks' exposure (groups 1, 2, 3 and 4) or were maintained as controls (groups 5, 6, 7 and 8). At week 11, the animals were inoculated with Hp (groups 1, 2, 5 and 6) or the vehicle alone (groups 3, 4, 7 and 8), and after week 12, animals were fed a 10% high salt diet (groups 1, 3, 5 and 7) or the control diet (groups 2, 4, 6 and 8). At week 50, the incidence of adenocarcinomas in group 1 (32.1%, 6 well-differentiated, 2 poorly-differentiated adenocarcinomas, and one signet-ring cell carcinoma) was significantly higher than in groups 3 (0%) (P < 0.005) and 4 (0%) (P < 0.01). The incidence of adenocarcinomas in group 2 (11.8%, one well-differentiated adenocarcinoma, and one signet-ring cell carcinoma) was also higher than in groups 3 and 4. A high-salt diet enhanced the effects of Hp infection on gastric carcinogenesis, and these two factors acted synergistically to promote the development of stomach cancers. Moreover, Hp infection promoted gastric carcinomas more than the high-salt diet.

Helicobacter pylori (Hp) infection is an important factor in human gastric disorders. Mongolian gerbils can be easily infected with Hp and represent excellent experimental models to clarify the role of Hp in chronic active gastritis, peptic ulcers, intestinal metaplasia, and gastric carcinoma. We have proved the enhancing effects of Hp infection on all histological types of gastric cancers in Mongolian gerbils exposed to chemical carcinogens. Heterotopic proliferative glands (HPGs) also frequently develop with Hp infection in the glandular stomach of infected gerbils, with a slightly dysplastic change of constituent cells. Distinguishing reversible inflammatory lesions from true neoplasms upon eradication is necessary for further biological or histochemical investigations using this model. We employed an experimental model of long-term Hp infection and eradication in gerbils. HPGs finally developed with a phenotypic shift of intestinalization with Paneth cells. After eradication, HPGs were obviously reduced, and gastric lesions in mucosa also improved with few remnants of the former injury. This shows that reversible HPGs are frequently induced solely by Hp infection in this animal species, and are related to severe gastritis, rather than being malignant in character. Thus, distinguishing reversible lesions from true neoplasms is necessary to investigate the relationship of Hp infection and gastric carcinogenesis in this animal model.

Helicobacter pylori (Hp) was concluded to be 'a definite carcinogen' by WHO/IARC in 1994. We have demonstrated that Hp infection enhances chemical carcinogen-induced stomach carcinogenesis in Mongolian gerbils (MGs) using N-methyl-N'-nitro-N-nitrosoguanidine or N-methyl-N-nitrosourea. Not only well-differentiated but also poorly differentiated and signet ring cell types of cancers are observed, mimicking the human case. Eradication of Hp was found to be effective of preventing enhancing effects. Hp infection alone, without chemical carcinogens, caused submucosal proliferating lesions, but not gastric carcinomas, in contrast to reports that Hp infection alone may act on a complete carcinogen. Precise pathological assessment is required to solve this controversy. Here we demonstrate alleviation of Hp induced gastric lesions with eradication in MGs.

To explore the 'causal link' between Helicobacter pylori(Hp) infection and stomach carcinogenesis, we have established experimental models of stomach carcinogenesis in Mongolian Gerbils(MGs) using the chemical carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine(MNNG) and N-methyl-N-nitrosourea(MNU). The incidence of adenocarcinoma was significantly higher in animals treated with Hp than in the controls. Eradication of Hp was effective in reducing the incidence of adenocarcinoma. No gastric carcinoma was found without any chemical carcinogen. Hp infection enhances glandular stomach carcinogenesis not only of well-differentiated type but also poorly differentiated type and signet ring cell type. Eradication of Hp, apparently a gastric promoter rather than gastric carcinogen, may be useful as a measure for prevention of stomach cancer.

To investigate the nature of the link between Helicobacter pylori (Hp) infection and stomach carcinogenesis, a study of the glandular stomach of Mongolian gerbils (MGs) was performed. MGs were treated with N-methyl-N-nitrosourea (MNU), followed by inoculation with Hp (groups 1 and 2) or without Hp (group 3), or infected with Hp (groups 4 and 5) or inoculation without Hp (group 6) followed by MNU administration. At week 21, the animals in groups 2 and 5 underwent an eradication procedure. At week 50, the incidences of adenocarcinomas in group 1 (15 of 23) and group 4 (9 of 26) were significantly higher than in group 3 (1 of 15) and group 6 (1 of 18), respectively. Moreover, those in group 2 (5 of 24) and group 5 (2 of 22) were lower than in groups 1 and 4, respectively. This study shows that Hp eradication may be useful as a prevention approach against stomach cancer.