Carcinogenesis of Helicobacter pylori

doi:10.1053/j.gastro.2007.06.026

Gastroenterology

Volume 133, Issue 2, August 2007, Pages 659-672

https://doi.org/10.1053/j.gastro.2007.06.026 Get rights and content

Helicobacter infection is the leading cause of gastric cancer worldwide. Infection with this ubiquitous bacterium incites a chronic active immune response that persists for the life of the host, in the absence of antibiotic-induced eradication. It is the combination of bacterial factors, environmental insults, and the host immune response that drives the initiation and progression of mucosal atrophy, metaplasia, and dysplasia toward gastric cancer. Although it may seem intuitively obvious that removing the offending organism would negate the cancer risk, this approach is neither feasible (half of the world harbors this infection) nor is it straightforward. Most patients are infected in childhood, and present with various degrees of mucosal damage before any therapy. This review outlines the histologic progression of human Helicobacter infection from the early stages of inflammation through the development of metaplasia, dysplasia, and, finally, cancer. The effects of dietary and bacterial eradication therapy on disease progression and lesion reversibility are reviewed within the context of population studies and compared between study designs and populations tested. Eradication studies in the mouse model of infection prevents the formation of gastric cancer, and allows regression of established lesions, providing a useful model to study interaction between bacterium, environment, and host, without the difficulties inherent in human population studies. Recent advances in identifying the bone marrow-derived stem cell as the cell of origin of Helicobacter-induced gastric cancer in the murine model are discussed and interpreted in the context of human disease, and implications for future treatment are discussed.

Section snippets

Precancerous Cascade

The presence of gastric lesions outside the tumor was described first in gastrectomy specimens and was later examined more in detail when biopsies taken by flexible gastroscopes became generally available. It then became possible to develop a model of gastric carcinogenesis that has been generally accepted.⁴ Long-term follow-up of cohorts in high-risk populations has documented the dynamics of the precancerous process5, 6 (Table 1). The basic components of the process are chronic active

Natural History of Precursor Lesions

Follow-up of patients with precursor lesions in populations at high cancer risk has thrown light on the dynamics of the process. The progression of these lesions follows a pattern of steady state, with episodes of progression to more advanced lesions and episodes of regression to less advanced lesions. Table 1 is based on the experience of a cohort of 1422 subjects followed up for an average of 5 years in the high-risk region of Narino, Colombia.⁵ Although there may be sampling errors owing to

Prevention Trials

The slow progression of precancerous lesions has stimulated cancer prevention trials in several countries. These trials have addressed etiologic factors identified in epidemiologic studies, namely, the deficient intake of antioxidants and the infection with H pylori.

Two trials, one in a population from Venezuela¹⁹ and the other in a population from Finland²⁰ who used antioxidants in the form of food supplements, have reported negative results. These trials suffered from a number of problems

Mechanisms of H pylori Carcinogenesis

After the International Agency for Research on Cancer (IARC) classification of H pylori infection as a class I carcinogen, a considerable amount of confirmatory evidence has accumulated. The 1994 IARC report was based entirely on epidemiologic evidence.³¹ It explicitly stated that experimental evidence was needed. The mechanism of the initial insult to DNA molecules is unknown; however, the leading hypothesis is that the neoplastic outcome is related to oxidative stress, as represented by the

Animal Models for Studying Helicobacter-Induced Gastric Mucosal Changes

The human studies outlined raise the important question: At what point are mucosal lesions reversible, and what is the “point of no return”—when they are irreversible and/or progressive? Studies in humans aimed at addressing the role of eradication therapy in the regression of gastric lesions and the prevention of gastric cancer are problematic for multiple reasons, including variations in patient populations, the inability to determine the length of time patients were infected, and the lack of

The C57BL/6 Mouse Model to Study the Natural History of Helicobacter Infection and the Effects of Eradication Therapy

Helicobacter felis infection in the C57BL/6 mouse model reproducibly results in the classic sequence of histologic changes seen in human infection; chronic gastritis, atrophy, metaplasia, dysplasia, and adenocarcinoma, with adenocarcinoma occurring in 100% of mice that were infected for 15 months.37, 38, 39 All strains of mice appear susceptible to infection; however, strains vary dramatically in their susceptibility to mucosal damage. This inherent susceptibility or resistance is based on the

The Mouse Model Is a Useful Tool to Define Signaling Events Underlying Histologic Alterations

The reversibility of the metaplastic and dysplastic lesions after bacterial eradication suggests that cellular differentiation in the gastric mucosa depends on the local environment and may not be due to genetic alterations per se early on. Important environmental conditions include bacterial factors as well as components of the host immune environment (reviewed by Jean Crabtree and Keith Wilson [Gastroenterology 2007;133:288–308]). Indeed, the pattern of inflammatory cytokines within the

Cancer Stem Cells

In general, cancer can be thought of as an abnormal organ, composed of multiple diverse cell types in various stages of differentiation and with different proliferative capacities. Recently, a population of cancer cells within tumors has been identified that serves to provide all of the cancer cells of the tumor, termed the “cancer stem cell.”55, 56 The identity of the cancer stem cell has remained relatively elusive until recently, when several groups prospectively identified the cancer stem

Bone Marrow-Derived Cells as a Source of the Cancer Stem Cell

Indeed, there is increasing support of the BMDC as a cancer stem cell beyond the theoretical and circumstantial. If one looks closely at the phenotype and surface marker profile of identified cancer stem cells and compares these to markers found on BMDC, there are very interesting similarities. Both cell types may express CD4467, 68 and the ABC transporter Bcrp1/ABCG269, 70 on the cell surface, endowing both cell types with the stem cell-side population phenotype.69, 70, 71, 72 Also, similar

Evidence for a BMDC as the Cancer Stem Cell in Helicobacter-Induced Gastric Cancer

Chronic inflammation is a key factor in the pathogenesis of gastric cancer, providing a useful model system for determining if a BMDC, as the ultimate uncommitted adult stem cell, could function as the cell for malignant transformation. For these experiments, the well-described C57BL/6 mouse model of Helicobacter-induced gastric cancer,³⁷ which closely mimics human infection and cancer formation, was used. As in humans, gastric cancer in the mouse rarely is encountered in the absence of

Summary and Future Directions

Human and experimental evidences coincide in pointing to a lengthy gastric precancerous process with sequential stages of chronic inflammation, atrophy, metaplasia, and dysplasia. The initial stages of inflammation and atrophy create an abnormal microenvironment favoring engraftment of BMDC. These cells do not enter in the pathway of complete differentiation and follow a program of uncontrolled replication, progressive loss of differentiation, and eventual neoplastic invasive behavior.

These

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: Supported in part by NIH funding grants CA113564, CA119061 (to J.H.), and DOI-OA-028842 (to P.C.).

View full text

Review in basic and clinical gastroenterologyCarcinogenesis of Helicobacter pylori

Section snippets

Precancerous Cascade

Natural History of Precursor Lesions

Prevention Trials

Mechanisms of H pylori Carcinogenesis

Animal Models for Studying Helicobacter-Induced Gastric Mucosal Changes

The C57BL/6 Mouse Model to Study the Natural History of Helicobacter Infection and the Effects of Eradication Therapy

The Mouse Model Is a Useful Tool to Define Signaling Events Underlying Histologic Alterations

Cancer Stem Cells

Bone Marrow-Derived Cells as a Source of the Cancer Stem Cell

Evidence for a BMDC as the Cancer Stem Cell in Helicobacter-Induced Gastric Cancer

Summary and Future Directions

Lancet

Mod Pathol

Lab Invest

Am J Clin Nutr

Gastroenterology

Gastroenterology

J Biol Chem

Gastroenterology

Gastroenterology

Gastroenterology

Crit Rev Oncol Hematol

Trends Cell Biol

Cell

Cell

Gastroenterology

Cell

On the role of heterotopias of the intestinal epithelium in the pathogenesis of gastric cancer

Acta Pathol Microbiol Scand

The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinomaAn attempt at a histo-clinical classification

Acta Pathol Microbiol Scand

Carcinoma arising from areas of intestinal metaplasia in the gastric mucosa

Br J Cancer

Gastric precancerous process in a high risk population: cohort follow-up

Cancer Res

Studies of patients with atrophic gastritis: a 10–15-year follow-up

Scand J Gastroenterol

Long term follow up of patients treated for Helicobacter pylori infection

Gut

Classification and grading of gastritisThe updated Sydney System

Am J Surg Pathol

The risk of stomach cancer in patients with gastric or duodenal ulcer disease

N Engl J Med

Incomplete sulphomucin-secreting intestinal metaplasia for gastric cancerPreliminary data from a prospective study from three centres

Gut

Distribution of marker enzymes and mucin in intestinal metaplasia in human stomach and relation to complete and incomplete types of intestinal metaplasia to minute gastric carcinomas

J Natl Cancer Inst

Differentiation of the gastric mucosa IIIAnimal models of oxyntic atrophy and metaplasia

Am J Physiol Gastrointestinal Liver Physiol

Identification of spasmolytic polypeptide expressing metaplasia (SPEM) in remnant gastric cancer and surveillance postgastrectomy biopsies

Dig Dis Sci

Gastric dysplasia: the Padova international classification

Am J Surg Pathol

The detection, surveillance and treatment of premalignant gastric lesions related to Helicobacter pylori infection

Helicobacter

Chemoprevention of precancerous gastric lesions with antioxidant vitamin supplementation: a randomized trial in a high-risk population

J Natl Cancer Inst

Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population

J Natl Cancer Inst

Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-Helicobacter pylori therapy

J Natl Cancer Inst

Helicobacter pylori infection and the development of gastric cancer

N Engl J Med

Helicobacter pylori eradication prevents the development of gastric cancer—results of a long-term retrospective study in Japan

Aliment Pharmacol Ther

Helicobacter pylori eradication and gastric preneoplastic conditions: a randomized, double-blind, placebo-controlled trial

Cancer Epidemiol Biomarkers Prev

Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial

JAMA

Factors predicting progression of gastric intestinal metaplasia: results of a randomised trial on Helicobacter pylori eradication

Gut

Randomized double-blind factorial trial of three treatments to reduce the prevalence of precancerous gastric lesions

J Natl Cancer Inst

Duration of exposure, a neglected factor in chemoprevention trials

Cancer Epidemiol Biomarkers Prev

Cigarette smoking and bronchial carcinoma: dose and time relationships among regular smokers and lifelong non-smokers

J Epidemiol Community Health

Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: effect of antibiotics and antioxidants

Review in basic and clinical gastroenterology
Carcinogenesis of Helicobacter pylori