Carcinogenesis and infection with Helicobacter pylori.
Gianina MicuFlorica StăniceanuSabina ZuracAlexandra BastianEliza GrămadaLuciana NichitaCristiana PoppLiana SticlaruR AndreiClaudiu Socoliuc
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Abstract:
It was accepted several years ago that, in the carcinogenesis process of human cancers, biologic agents, especially the viruses, are playing an etiologic role. This is the case of lymphomas (retroviruses), hepatocarcinoma (hepatic viruses) and cervical carcinoma (papilloma viruses). Helicobacter pylori is the first bacteria recognized as a first class carcinogen for gastric cancer. Nevertheless, comparing with the most validated human carcinogens, the activity of H. pylori is very little studied. As a consequence, at this moment, in its case, explanation of carcinogenesis mechanism is more or less hypothetical.Keywords:
Helicobacter
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Gastric cancer in the absence of strategies implemented for early detection continues to have a dismal prognosis. There are limited options for a curative therapy once patients present with clinical manifestations of this malignant disease. Helicobacter pylori (H. pylori) infection plays a key role in gastric carcinogenesis, supported by epidemiological, preclinical and clinical studies. The recognition of H. pylori infection as a critical risk factor in the development of gastric cancer opens the chance for new venues in prevention strategies.
Pathogenesis
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Helicobacter pylori has been implicated in stimulation of immune system, development of autoimmune endocrinopathies as autoimmune thyroiditis (AT) and on other hand induction of immunosupresion activates gastric and extra-gastric diseases such as gastric ulcer or cancer. It causes persistent lifelong infection despite local and systemic immune response. Our results indicate that Helicobacter pylori might cause inhibition of the specific cellular immune response in Helicobacter pylori-infected patients with or without autoimmune diseases such as AT. We cannot also declare the carcinogenic effect in oropharynx. However the association of any infection agents and cancerogenesis exists. The adherence of Helicobacter pylori expression and enlargement of benign lymphatic tissue and the high incidence of the DNA of Helicobacter pylori in laryngopharyngeal and oropharyngeal cancer is reality. LTT appears to be a good tool for detection of immune memory cellular response in patients with Helicobacter pylori infection and AT. All these complications of Helicobacter pylori infection can be abrogated by successful eradication of Helicobacter pylori.
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H. pylori가 공식적인 발암인자로 지정된 이후, 많은 연구가 H. pylori감염과 위암종 발생간의 연관관계를 지지해 왔다. 비록 몇몇 연구가 위암종 발생에 대한 H. pylori 감염의 부정적인 영향에 대한 증거를 제공하기는 했지만, 이들 연구가 H. pylori 감염률을 과소평가했다는 새로운 증거들이 제시되고 있다. 이 종설에서는 위암과 H. pylori의 역학적인 생태, H. pylori 감염과 위암종 발생의 연관관계를 지지하는 증거들, 제시된 위암종 발생의 기작, 그리고 H. pylori 감염의 위암종 발생에서의 잠재적인 병리학적 역할을 기존 연구들을 바탕으로 살펴보았다. 결론적으로 H. pylori 감염은 위암종 발생과 긍정적인 연관관계를 가진다는 것을 밝힐 수 있었다. Ever since the World Health Organization classified Helicobacter pylori as a class I carcinogen, a variety of discussions over the actual role of H. pylori infection in gastric carcinogenesis has existed. Although a majority of researches support the positive correlation between H. pylori infection and the development of gastric cancer, many aspects of this association are yet uncertain, and some data even suggest that there may be no correlation between H. pylori infection and gastric carcinogenesis. However, there are proofs indicating these reports underestimated the prevalence of H. pylori infection and therefore, the association of the infection and gastric adenocarcinoma. In this report, I reviewed the epidemiology of H. pylori and gastric cancer, evidence supporting and against the positive correlation of the infection and the disease, and the possible pathological role H. pylori infection may have in gastric carcinogenesis referring particular to published literature. As a conclusion, despite a few reports of a possible negative or no relationship between gastric cancer and H. pylori infection, I was able to find that H. pylori infection did have a pathological role in the development of gastric cancer.
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Among the suspected bacterial causes of cancer, H. pylori is the agent more consistently linked to malignancy. After its discovery in 1983 and the later confirmation as the leading cause of chronic gastritis, several studies were performed to prove an association between H. pylori infection and gastric carcinoma. The epidemiological data have been so strong that in 1994 the International Association for Research on Cancer stated that "there was sufficient evidence" to classify H. pylori as a group I carcinogen in humans. However, the exact mechanisms underlying the link between H. pylori infection and gastric carcinoma remain still to be elucidated. The natural history of H. pylori infection shows that, although roughly half of the world's human population bears the organism, only a minority of individuals develop clinically important outcomes (e.g. peptic ulcer, lymphoproliferative diseases, atrophic gastritis and gastric carcinoma): host's genetic make-up, duration of infection, diet and differences between H. pylori strains have been proposed as factors potentially able to influence the outcomes in different individuals. The damaging agents by which H. pylori could promote gastric carcinogenesis are produced either by the organism or as a consequence of the host inflammatory response to the infection. Gastric mucosal chronic damage may, therefore, lead to changes in the pattern of epithelial cell kinetic (increase in cell proliferation and induction of apoptosis) in gastric glands which may induce DNA injury with irreversible genetic lesions. Finally, a direct association between H. pylori infection and the induction of gastric carcinoma has been recently demonstrated in an animal model, giving further credence to the role of this organism in gastric carcinogenesis.
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H. pylori has been included as a definite biological carcinogen by WHO/ IARC. H. pylori is thought to play a role in the gastritis-metaplasia-carcinoma sequence by inducing atrophic gastritis. Clinical and epidemiological studies have shown a close association between H. pylori infection and gastric cancer. Yet, experimental evidence is equivocal. Epidemiological evidence also suggests that there are significant variable(s) other than H. pylori infection in gastric carcinogenesis. Clearly many questions regarding the role of H. pylori in gastric carcinogenesis have been left for further study. The authors have summarized these aspects together with their experimental results.
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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.
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In spite the fact that H. pylori infection might be the causative organisms of acute and chronic gastritis, peptic ulcer diseases and the definition as the class I carcinogen by WHO IARC, still debates exist about the relationship between H. pylori and gastric carcinogenesis. Epidemiological and animal studies demonstrated a link between gastric cancer and chronic infection with H, pylori, but the exact mechanism responsible for the development of gastric cancer in H. pylori-infected patients still remain obscure. In order to declare the clear association, definate evidences like that decrement in the incidence of gastric cancer after the eradication of H. pylori in designated area compared to noneradicated region or the blockade of specific mechanism acting on the carcinogenesis by H. pylori infection. The other way is to identify the upregulating oncogenes or downregulating tumor suppressor genes specifically invovled in H. pylori-associated carcinogenesis. For that, we established the animal models using C57BL/6 mice strain. Already gastric carcinogenesis was developed in Mongolian gerbils infected with H. pylori, but there has been no development of gastric cancer in mice model infected with H. pylori after long-term evaluation. Significant changes such as atrophic gastritis were observed in mice model. However, we could observe the development of mucosal carcinoma in the stomach of transgenic mice featuring the loss of TGF-beta sig naling by the expressions of dominant negative forms of type II receptor specifically in the stomach. Moreover, the incidence of gastric adenocarcinoma was significantly increased in group administered with both MNU and H. pylori infection than MNU alone, signifying that H. pylori promoted the gastric carcinogenesis and there might be host susceptibility genes in H. pylori-associated gastric carcinogenesis. Based on the assumption that chronic, uncontrolled inflammation might predispose to carcinogenesis, there have been several evidences showing chronic atrophic gastritis predisposed to gastric carcinogenesis in H. pylori infection. Although definite outcome of chemoprevention was not drawn after the longterm administration of anti-inflammatory drug in H. pylori infection, the actual incidence of atrophic gastritis and molecular evidence of chemoprevention could be obtained. Selective COX-2 inhibitor was effective in decreasing the development of gastric carcinogenesis provoked by H. pylori infection and carcinogen like in chemoprevention of colon carcinogenesis.
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Gastric carcinogenesis involves a slow but continuous, stepwise evolution from superficial gastritis to glandular atrophy, metaplasia, dysplasia, and finally, to adenocarcinoma. In 1994, the International Agency for Research on Cancer defined Helicobacter pylori (H. pylori) as a group I carcinogen. Evidence supporting a causal association has been demonstrated by epidemiological data as well as by experimental animal models. The process of carcinogenesis, which may well extend over decades, provides an excellent opportunity for prevention or early detection of the events preceding development of the neoplasm. This is especially true because, at present, H. pylori can be readily treated. Despite this, the prognosis for gastric cancer is poor and, in most industrialised countries, the survival is only 10% after 5 years from diagnosis. The sole exception is Japan where this malignancy is often identified at an early stage when cure by radical surgery is more probable.
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