Development of poorly differentiated adenocarcinoma and carcinoid due to long-term Helicobacter pylori colonization in Mongolian gerbils

Hirayama, Fumihiro; Takagi, Shiro; Iwao, Eiji; Yokoyama, Yoshito; Haga, Keiichiro; Hanada, Shuichi

doi:10.1007/s005350050295

Cited by 107 publications

(78 citation statements)

References 15 publications

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“…To our knowledge, this is the first report of expression of endocrine and mucous cell markers observed periodically in the glandular stomach of H. pylori-infected MG, although several studies have shown that long-term H. pylori colonization produces hyperplasia of gastrin-producing antral G-cells and carcinoid tumors in MG. (7,9,26) In the present study, the immunohistochemical data demonstrated that the numbers of CgA-and gastrin-positive cells in H. pylori-infected groups was increased significantly compared with the non-infected condition, but both demonstrated a gradual decrease over time, despite the lack of any significant variation in CgA or gastrin mRNA expression between Hp(+)-50-week and Hp(+)-100-week. In humans, there have been several reports of no significant differences in the number of G-cells and G-cell density in the stomach mucosa between H. pyloriinfected and -uninfected healthy volunteers, (27)(28)(29) although the number of G-cells was significantly less in patients with both H. pylori infection and duodenal ulcer than in either infected or uninfected controls.…”

Section: Discussionsupporting

confidence: 47%

“…(4 -6) In the MG model, alterations in the endocrine cell population are also found during H. pylori infection. (7)(8)(9) Regarding the cellular differentiation of endocrine cells in the gastrointestinal tract, gastrin is detectable predominantly in the pyloric glands of the stomach, whereas gastric inhibitory polypeptide (GIP) is characteristic of the duodenum and small intestine. (10)(11)(12)(13)(14) Therefore, gastrin could be a gastric endocrine cell marker, in contrast to GIP as an intestinal example.…”

Section: T He Mongolian Gerbil (Mg) Is Useful For Examining the Link mentioning

confidence: 99%

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Helicobacter pylori infection stimulates intestinalization of endocrine cells in glandular stomach of Mongolian gerbils

Takenaka¹,

Tsukamoto²,

Mizoshita³

et al. 2006

Cancer Science

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Intestinal metaplasia has been investigated extensively as a possible premalignant condition for stomach cancer but its pathogenesis is still not fully understood. In the present study, we examined the relationship between endocrine and mucous cell marker expression periodically after (1) In our animal model, we have previously demonstrated that eradication at early stages of inflammation is effective in preventing H. pylorirelated stomach carcinogenesis.(2) Wong et al. (3) have demonstrated similar results in a human randomized-controlled trial of H. pylori eradication in China, and pointed out the importance of analyses of the factors that determine irreversibility − in other words, the point of no return. Thus, for the prevention of stomach cancer in MG, it is very important to estimate the histological and genetic alternations in the glandular stomach periodically and continuously after H. pylori infection, which is impossible in humans because of imprecise information on the time of infection with bacteria.Several studies have demonstrated that changes in endocrine and mucous cells are observed in intestinal metaplasia (IM) in the human pyloric mucosa associated with H. pylori infection. (4 -6) In the MG model, alterations in the endocrine cell population are also found during H. pylori infection.(7-9) Regarding the cellular differentiation of endocrine cells in the gastrointestinal tract, gastrin is detectable predominantly in the pyloric glands of the stomach, whereas gastric inhibitory polypeptide (GIP) is characteristic of the duodenum and small intestine.(10-14) Therefore, gastrin could be a gastric endocrine cell marker, in contrast to GIP as an intestinal example. (14) We have recently documented clear evidence that the phenotypes of endocrine cells are associated strongly with those of mucous cells in human IM as well as in normal gastric glands, (14) supporting the hypothesis that abnormal differentiation of stem cells underlies the development of IM in the human stomach.(15) With investigations of the histogenesis of H. pylori-related lesions, it is very interesting to focus on relationships between endocrine and mucous cells periodically in the MG model from the viewpoint of phenotypic expression.In the present study, we therefore examined the expression of endocrine cell markers by immunohistochemistry and the quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) using a gland isolation technique, and evaluated the relationship between endocrine and mucous cell marker expression at 50, 75 and 100 weeks after H. pylori infection in the MG model. Materials and MethodsSamples. Seventy specific pathogen-free male MG (Seac Yoshitomi, Fukuoka, Japan), aged 7 weeks, and H. pylori (ATCC 43504; American Type Culture Collection, Rockville, MD, USA) were used for this study. The bacteria were grown from freezer stocks for 72 h and harvested in Brucella broth. Samples (0.8 mL) containing approximately 1.0 × 10 8 colonyforming units per mL were used as the inoculum, as describe...

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Section: Discussionsupporting

confidence: 47%

Section: T He Mongolian Gerbil (Mg) Is Useful For Examining the Link mentioning

confidence: 99%

Helicobacter pylori infection stimulates intestinalization of endocrine cells in glandular stomach of Mongolian gerbils

Takenaka¹,

Tsukamoto²,

Mizoshita³

et al. 2006

Cancer Science

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“…Interestingly, in patients treated with a proton pump inhibitor the degree of initial hypergastrinemia is predictive of the later development of gastric atrophy (27), which in turn could enhance the hypergastrinemia. A contribution of gastrin toward parietal cell loss and gastric atrophy is important, because it is known that gastric atrophy is associated with development of both gastric cancer (28) and ECL cell carcinoids (29) in Mongolian gerbils. This also applies to human ECL cell carcinoids (30,31) and gastric adenocarcinomas (32).…”

Section: Discussionmentioning

confidence: 99%

ECL-Cell Derived Gastric Cancer in Male Cotton Rats Dosed with the H2-Blocker Loxtidine

et al. 2004

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Spontaneously hypergastrinemic cotton rats (Sigmodon hispidus) develop tumors that have the phenotype of an adenocarcinoma but most likely originate from the enterochromaffin-like (ECL) cells. Among inbred animals ϳ50% of the females, but <1% of males develop spontaneous gastric carcinomas. Gastrin is the principle carcinogen in this model, as >4 months of hypergastrinemia results in carcinoma, but a gastrin receptor antagonist prevents carcinomas. Carcinomas can also be induced by partial corpectomy. In the present study, the insurmountable H2-receptor antagonist loxtidine (200 mg/kg/day) was given to male cotton rats for 6 months. The loxtidine-dosed animals developed hypergastrinemia, whereas control animals remained normogastrinemic. At termination, 4 of 5 cotton rats had cancer located to the oxyntic mucosa, whereas 1 animal had dysplasia. The gastric mucosa of all of the control animals was normal. In the dysplastic mucosa of loxtidine-dosed animals there was a marked increase in chromogranin A-positive cells, where numerous groups of cells also stained positive with the Sevier-Munger technique. In areas of high proliferation and cancer there were also histidine decarboxylase, chromogranin A, and Sevier-Munger-positive cells, altogether indicating an ECL cell origin of the tumors. This represents an interesting animal model where ECL cell-derived gastric cancer can be induced by pharmacological acid inhibition in 6 months.

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“…The HP infection rate is higher in Japan than in Western countries, with nearly all cases of GC occurring in subjects with underlying HP-related chronic gastritis. HP infection is widely accepted as a major risk factor for the development of GC and its precursor lesions, based on extensive evidence derived from many studies (Blaser et al, 1995;EUROGAST Study Group, 1993;Forman et al, 1991;Hirayama et al, 1999;Honda et al, 1998;Huang et al, 1998;Nomura et al, 1991;Parsonnet et al, 1991;Shimizu et al, 1999;Sipponen et al, 1992;Sugiyama et al, 1998;Talley et al, 1991;Tokieda et al, 1999;Uemura et al, 2001;Watanabe et al, 1998;Zheng et al, 2004). However, in countries such as Japan, where the HP infection rate is high, prediction of GC risk based solely on the presence or absence of HP infection does not offer sufficient specificity.…”

Section: Introductionmentioning

confidence: 99%

Gastric Cancer Risk Diagnosis and Prevention in Subjects with Helicobacter pylori-related Chronic Gastritis

Enomoto¹,

Watanabe²,

Mukoubayashi³

et al. 2011

Gastritis and Gastric Cancer - New Insights in Gastroprotection, Diagnosis and Treatments

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GC risk diagnosis based on the natural history of HP-related chronic gastritisNovel risk markers to identify GC high-risk groups based on a detailed natural history of HP-related chronic gastritis have long been awaited. In this section, we discuss the emerging significance of serum PG as a GC risk marker for more precise identification of GC high-risk groups. Serum PG testHP-related chronic gastritis usually starts in the antrum and expands proximally towards the body of the stomach (Kimura, 1972;Tatsuta et al., 1973). As several studies dealing with endoscopic biopsies or chromoendoscopic testing have found that progression of chronic atrophic gastritis (CAG) increases the risk of cancer (Meister et al., 1979;Sipponen et al., 1985;Siurala et al., 1966;Tatsuta et al., 1993;Testoni et al., 1987), accurate and reliable evaluation of the extent of CAG is considered important for identifying individuals at high risk of cancer. However, accurately diagnosing the extent of CAG based on a few biopsy samples is difficult, because CAG together with intestinal metaplasia is a multifocal process. Furthermore, histological diagnosis of gastric atrophy depends on subjective judgment without a gold standard (Guarner et al., 1999;Plummer et al., 1997). A test for CAG progression that is more convenient, free of discomfort or risk, economical and based on objective parameters is needed. PG is the inactive precursor of pepsin, a digestive enzyme specifically produced in the stomach. Immunologically, two isozymes exist (Kageyama, 2003). PGI is produced by chief cells and mucus neck cells of the gastric fundic glands. In contrast, PGII is produced not only by chief cells and mucus neck cells, but also in cardiac glands, pyloric glands, and Brunner's glands, with localization of producing cells in a wide range from the stomach to the duodenum. The majority of PG produced (about 99%) is secreted in the stomach lumen and functions as a digestive enzyme. However, a small amount of PG (about 1%) is also present in blood and can be evaluated by measuring serum PG levels. Serum PG levels are generally agreed to reflect the morphological and functional status of the stomach mucosa (Hirschowitz, 1957;Samloff et al., 1982). In an endoscopic study with Congo red staining, we have shown a strong correlation between an increase in glandular boundary, associated with diagnosed progression of gastric mucosal atrophy, and stepwise reductions in serum PGI levels and the PGI/PGII ratio ( Fig. 1) (Miki et al., 1987). In other words, by measuring serum PGI and the PGI/II ratio, the progression of CAG, which is involved in GC carcinogenesis, can be objectively evaluated (Ichinose et al., 2001). In addition, during HP infection, serum PGI and PGII increase, and the PG I/II ratio decreases. These findings are improved after eradication treatment (Furuta et al., 1997) and are useful as gastric mucosal inflammatory markers. Several criteria are used in the serum PG test. As criteria for GC screening, the combination of PGI ≤70 ng/ml and PGI/II ratio ≤3.0...

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Development of poorly differentiated adenocarcinoma and carcinoid due to long-term Helicobacter pylori colonization in Mongolian gerbils

Cited by 107 publications

References 15 publications

Helicobacter pylori infection stimulates intestinalization of endocrine cells in glandular stomach of Mongolian gerbils

Helicobacter pylori infection stimulates intestinalization of endocrine cells in glandular stomach of Mongolian gerbils

ECL-Cell Derived Gastric Cancer in Male Cotton Rats Dosed with the H2-Blocker Loxtidine

Gastric Cancer Risk Diagnosis and Prevention in Subjects with Helicobacter pylori-related Chronic Gastritis

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