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Helicobacter pylori and gastric carcinogenesis: An experimental study of some preneoplastic events
Linköping University, Department of Biomedicine and Surgery. Linköping University, Faculty of Health Sciences.
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Half the population in the world is chronically infected with H.pylori. This infection has been proven to be associated with gastritis, duodenal and gastric ulcers but also with gastric cancer and MALT-lymphoma. The aims of this thesis were to explore some possible mechanisms by which H.pylori may contribute to the onset of gastric cancer.

The first approach was to study whether H. pylori is mutagenic. Three different H.pylori strains (NCTC 11637, Ca 18, 13/12), all cagA and VacApositive, were studied with the Salmonella mutagenicity assay (the Ames test). No dose-response curve and no increase in revertants were seen. These results show that H. pylori is not likely to be mutagenic.

A special feature ofH.pylori gastritis is that it is practically always linked to inflammation with varying degrees of mucosal activity. Neutrophils and monocytes produce and liberate nitric oxide and oxygen radicals, which are capable of inducing mutations of DNA. In order to test if the bacterium alone or together with bile could affect lenkocytes to produce mutagenic substances, some in vitro experiments were performed. The Ames test was used on neutrophils from blood donors. The neutrophils· were exposed to H. pylori and/or bile. A time-dependent response was found, where neutrophils exposed for two hours or more showed significant mutagenic activity in 5 of 19 experiments. The combination with bile gave the highest response. In a follow up of these findings, no mutagenic activity was found in H. pylori-infected mouse mucosa when tested for mutagenic substances with the Ames test.

A second approach was to develop in vivo models of H. pylori gastritis by inoculating Wistar rats and C57BL/6 mice with species-adapted H. pylori strains. An increased cell proliferation was seen in infected animals whereas, the apoptotic rate was unaffected compared with non-infected controls. This different cell response may favour gastric carcinogenesis. Furthermore, H.pylori significantly promoted cell proliferation in rats exposed to bile, and in mice given the combination of MNNG and bile.

A third approach was to study the immunohistochemistry for the expression of the enzyme COX-2 and the protein Bcl-2 in rats receiving different combinations ofH.pylori, MNNG and bile. H.pylori enhanced Bcl-2 expression in antrum mucosa and also increased the COX-2 expression in corpus mucosa. The COX-2 expression correlated with increased cell proliferation in antrum but not with apoptosis. This change in COX-2 and Bcl-2 may also promote the development of neoplasia.

In conclusion, H. pylori may promote gastric carcinogenesis in several ways. Thus neutrophils that are accumulated in H.pylori-infected mucosa, may give rise to mutagenic substances. Moreover, H.pylori infection is associated with increased cell proliferation and unchanged apoptosis, which increases the risk for mitotic errors and mutations from endo- and exogenous carcinogens. The increased cell proliferation may be induced by a simultaneously increased COX -2 expression. The enhanced Bcl-2 expression in antrum that was corrolated to increased cell proliferation, also favours tumour development.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2001. , 88 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 681
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-25683Local ID: 10059ISBN: 91-7219-968-7 (print)OAI: oai:DiVA.org:liu-25683DiVA: diva2:246231
Public defence
2001-06-01, Wilandersalen, Regionsjukhuset, Örebro, 10:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-07Bibliographically approved
List of papers
1. Mutagenicity from neutrophils after challenge with Helicobacter pylori and bile
Open this publication in new window or tab >>Mutagenicity from neutrophils after challenge with Helicobacter pylori and bile
1997 (English)In: European Journal of Surgery, ISSN 1102-4151, E-ISSN 1741-9271, Vol. 163, no 10, 753-759 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To study some mechanisms involved in Helicobacter pylori (H. pylori)-induced gastric carcinogenesis.

DESIGN: In vitro study.

SETTING: Medical centre hospital, Sweden.

INTERVENTIONS: Mutagenicity in Ames' test of neutrophils challenged for 2 hours or more by two different strains of H. pylori. One strain designated NCTC 11637 by the National College of Type Cultures activated neutrophils to an oxidative burst and producing vacuolating cytotoxin, the other strain C-7050 lacked these abilities. Mutagenicity was also studied with sterile human gall bladder bile alone added to neutrophils or in combination with both neutrophils and H. pylori.

RESULTS: There was no increase in the number of revertants with the crude suspension or the supernatant of neutrophils challenged for 1 hour or less with H. pylori, bile, or the combination of both. However, in 5 out of 19 experiments there was significant mutagenicity after challenge of neutrophils for 2 hours or more with either strain of H. pylori, bile, or the combination of the two. The strongest mutagenicity was obtained after challenge over night (18 hours) with the combination of H. pylori and bile.

CONCLUSION: Mutagenicity occurs when neutrophils are challenged with H. pylori and bile. Factors other than reactive oxygen metabolites seem to be responsible.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81126 (URN)9373226 (PubMedID)
Available from: 2012-09-07 Created: 2012-09-07 Last updated: 2017-12-07Bibliographically approved
2. Helicobacter pylori is not mutagenic in Ames test
Open this publication in new window or tab >>Helicobacter pylori is not mutagenic in Ames test
2001 (English)In: Cancer Research, Therapy and Control, ISSN 1064-0525, Vol. 11, no 2, 167-173 p.Article in journal (Refereed) Published
Abstract [en]

Problem: Helicobacter pylori is classified as a class 1 carcinogen. However, the role of Helicobacter pylori in the initiation and promotion of gastric cancer is not known.

Methods: Mutagenicity has been measured in pure cultures of the cytotoxic Helicobacter pylori strains Ca 18 and NCTC 11637 and in extracts of Helicobacter pylori infected mouse stomach mucosa using the Salmonella mutagenicity test (Ames test). Chemiluminiscence assay was also used to verify the bacterial effect on inflammatory leukocytes.

Results: All Helicobacter strains studied induced a strong oxidative burst of polymorphonuclear leukocytes (PMNL). No direct or indirect mutagenic activity was found.

Conclusions: This confirm the concept that Helicobacter pylori is neither genotoxic per se nor indirectly by inducing mutagenic activity in gastric mucosa. Other mechanisms seems to play a role in the complex, multistep, and multifactorial process of gastric carcinogenesis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81127 (URN)
Available from: 2012-09-07 Created: 2012-09-07 Last updated: 2012-09-07Bibliographically approved
3. Helicobacter pylori, N-methyl-N'-nitro-N'-nitrosoguanidine, and bile modulate gastric cell kinetics in experimental cancer
Open this publication in new window or tab >>Helicobacter pylori, N-methyl-N'-nitro-N'-nitrosoguanidine, and bile modulate gastric cell kinetics in experimental cancer
2001 (English)In: Virchows Archiv, ISSN 0945-6317, E-ISSN 1432-2307, Vol. 439, no 5, 653-660 p.Article in journal (Refereed) Published
Abstract [en]

Helicobacter pylori infection is a risk factor for gastric cancer. How the bacterium contributes to this process is still unclear. We present a new Wistar rat model that was used to evaluate the effect of H. pylori on early preneoplastic events as judged from epithelial cell turnover and histopathological changes. One hundred and four rats were colonized with H. pylori and exposed MNNG (N-methyl-N'-nitro-N'-nitrosoguanidine) and/or taurocholic acid. Inflammation, goblet cell-like metaplasia, atrophy, dysplasia, and adenocarcinoma were scored in a blinded manner. Apoptotic cells were counted after staining with terminal uridine deoxynucleotidyl nick end labeling, and epithelial cell proliferation was determined by means of the Ki-67 labeling index. No early tumor enhancement with H. pylori could be found in ordinary histology. However, H. pylori significantly enhanced the epithelial cell proliferation compared with the control group, and the combination with taurocholic acid appeared to have a synergistic effect. MNNG significantly increased the normal gastric epithelial apoptosis. This increase was reduced in antral mucosa with H. pylori infection. The findings suggest that H. pylori, especially when combined with bile. has an influence on cell kinetics, contributing to the development of gastric cancer. The reduced apoptosis of MNNG also observed in infected animals indicates a dual function of H. pylori.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81128 (URN)10.1007/s004280100411 (DOI)
Available from: 2012-09-07 Created: 2012-09-07 Last updated: 2017-12-07Bibliographically approved
4. Effects of Helicobacter pylori and bile on N-methyl-N'-nitro-N'-nitrosoguanidine exposed antral mucosa of C57BL/6 mice
Open this publication in new window or tab >>Effects of Helicobacter pylori and bile on N-methyl-N'-nitro-N'-nitrosoguanidine exposed antral mucosa of C57BL/6 mice
2001 (English)In: Virchows Archiv, ISSN 0945-6317, E-ISSN 1432-2307, Vol. 439, no 5, 661-667 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to evaluate the early influence of Helicobacter pylori infection on cell kinetics in the antral mucosa of mice exposed to N-methyl-N'-nitro-N'-nitrosoguanidine (MNNG) and bile alone or in combinations. Four hundred and one C57BL/6 male and female mice were assigned into seven treatment groups and one non-treated control group. The gastric antrums were assessed by histology and immunohistochemistry for studies of cell proliferation and apoptosis at 32 and 44 weeks. One female and one male mouse had developed dysplastic adenomas in the pylorus mucosa and one male animal had dysplastic proliferation in the antrum. Only one of these lesions occurred in a H. pylori colonized animal. H. pylori infection significantly increased the cell proliferation at 32 weeks and promoted the cell proliferation in the MNNG and bile group at 44 weeks. Female mice showed less increase in cell proliferation than did the males. No change in apoptosis was seen in any of the groups. Bile had no promotional effect on cell proliferation. These results indicate that H. pylori infection has the potential to alter epithelial cell kinetics as well as antrum mucosa of an animal species that is regarded as resistant to MNNG. However, this change is not sufficient to promote the early development of neoplastic lesions.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81129 (URN)10.1007/s004280100456 (DOI)
Available from: 2012-09-07 Created: 2012-09-07 Last updated: 2017-12-07Bibliographically approved
5. Cyclooxygenase-2 and Bcl-2 expression in the stomach mucosa of Wistar rats exposed to Helicobacter pylori, MNNG and bile
Open this publication in new window or tab >>Cyclooxygenase-2 and Bcl-2 expression in the stomach mucosa of Wistar rats exposed to Helicobacter pylori, MNNG and bile
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Cyclooxygenase-2 (COX-2) and Bcl-2 may mirror different stages of gastric carcinogenesis, but the underlying mechanisms are not known. Thus the relation of COX-2 and Bcl-2 to known cell kinetics were studied in the glandular stomach mucosa of 104 Wistar rats given combinationsof H. pylori, MNNG (methyl-N'nitro-N-nitrosoguanidine) and bile.

COX-2 expression, Bcl-2 and cell proliferation (Ki-67) in antral and corpus mucosa were determined immunohistochemically. Apoptotic cells were detected by using terminal uridine deoxynucleotidyl nick end labeling technique.

Expression of COX-2 was found in the lower portion of glandular corpus epithelium and Bcl-2 positivity was mainly seen in the proliferative zone ofboth antmm and corpus mucosa. COX-2 in histologically normal-appearing corpus mucosa was associated with cell proliferation, atrophy and intestinal metaplasia in antmm and with Bcl-2 expression in corpus mucosa. No correlation was found between apoptosis and COX-2 or Bcl-2 expression. MNNG but not H. pylori significantly increased COX-2 in corpus mucosa. H.pylori, however, promoted the COX-2 expression in corpus when bile was added and Bcl-2 expression in antrum. These findings may indicate an early phase of gastric neoplasia in a state of increased cell proliferation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81130 (URN)
Available from: 2012-09-07 Created: 2012-09-07 Last updated: 2012-09-07Bibliographically approved

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