Yoshiharu Takenaka

Sox2 expression in human stomach adenocarcinomas with gastric and gastric‐and‐intestinal‐mixed phenotypes

Aims:  Other than ectopic expression of intestinal transcription factors, Cdx1 and Cdx2, the molecular mechanisms underlying gastric and intestinal phenotypes of human stomach adenocarcinomas have yet to be clarified in detail. We have reported that Sox2, an HMG‐box gastric transcription factor, is expressed in normal gastric mucosa and down‐regulated in intestinal metaplasia.

Emergence of spasmolytic polypeptide-expressing metaplasia in Mongolian gerbils infected with Helicobacter pylori

Spasmolytic polypeptide (TFF2)-expressing metaplasia (SPEM) is observed in mucosa adjacent to human gastric cancer and in fundic glands showing oxyntic atrophy in Helicobacter felis-infected mice. Mongolian gerbils infected with Helicobacter pylori (Hp) develop goblet cell intestinal metaplasia and adenocarcinoma, but the presence of SPEM has not been studied in gerbils. We therefore have sought to examine the development of metaplastic mucosal changes in Hp-infected Mongolian gerbils. Mongolian gerbils were assigned to either uninfected controls or infected with Hp at 17 weeks of age. The animals were killed at 17, 20, 26, 31, 41 and 56 weeks of age. Stomach sections were stained using antibodies for TFF2, intrinsic factor, H/K-ATPase, BrdU and MUC2. Dual immunofluorescence staining for TFF2 with intrinsic factor and for TFF2 with MUC2 was performed. In uninfected animals, no SPEM or intestinal metaplasia was observed. Infected gerbils developed SPEM initially in the intermediate zone along the lesser curvature and subsequently spread out towards the greater curvature. In the earlier stages of infection, SPEM glands demonstrated TFF2 and intrinsic factor double staining cells. However, after 35 weeks of infection, the number of double staining SPEM cells decreased. While early in infection SPEM organized in straight glands, in the later stages of infections, SPEM glands became distorted or dilated along with the development of gastritis cystica profunda that was TFF2 positive. Goblet cell intestinal metaplasia developed only late in the infection. Dual staining for TFF2 and MUC2 showed glands containing both SPEM- and MUC2-positive goblet cell intestinal metaplasia. SPEM develops early in Hp infection in Mongolian gerbils, and alterations in gland morphology arise from SPEM glands during the course of gastric infection with goblet cell intestinal metaplasia developing subsequent to SPEM.

Mutations and nuclear accumulation of β-catenin correlate with intestinal phenotypic expression in human gastric cancer

Aims:  Abnormal localization of β‐catenin is frequently observed in human gastric cancers. The aim of the present study was to evaluate relationships among gastrointestinal differentiation phenotypes, β‐catenin localization and mutations of Wnt signalling genes.

Gastric and intestinal phenotypes and histogenesis of advanced glandular stomach cancers in carcinogen-treated, Helicobacter pylori-infected Mongolian gerbils.

The Helicobacter pylori‐infected Mongolian gerbil (MG) has been established as an appropriate animal model for studies of stomach cancer development. However, there have hitherto been no data on the phenotypic classification of glandular stomach cancers in H. pylori‐infected and non‐infected MG. We therefore examined the phenotypes of 50 and six advanced glandular stomach cancers in H. pylori‐infected and non‐infected MG, respectively, as well as adjacent non‐neoplastic mucosa, using several gastrointestinal epithelial phenotypic markers. The lesions were divided phenotypically into 21 gastric, 24 gastric‐and‐intestinal mixed, four intestinal and one null types, with 90.0% of the lesions harboring gastric elements and 56.0% demonstrating intestinal phenotypic expression in H. pylori‐infected MG. All six lesions were classified as gastric type in non‐infected MG. There was no clear correlation with the presence of intestinal metaplasia in surrounding mucosa. In conclusion, our data suggest that most advanced adenocarcinomas retain a gastric cellular phenotype in the glandular MG stomach. Thus, it might be proposed that intestinal metaplasia is a paracancerous phenomenon rather than a premalignant condition. H. pylori infection may trigger intestinalization of both stomach cancers and non‐neoplastic mucosa. (Cancer Sci 2006; 97: 38 – 44)

Inhibitory effect of nordihydroguaiaretic acid, a plant lignan, on Helicobacter pylori‐associated gastric carcinogenesis in Mongolian gerbils

Recent epidemiological studies have demonstrated that consumption of certain natural products can lower cancer risk in humans. For example, plant‐derived lignans have been shown to exert chemopreventive effects against cancer in vitro and in vivo. In the present study, the effects of three such lignans, termed arctiin, arctigenin, and nordihydroguaiaretic acid (NDGA), on the proliferation of Helicobacter pylori and the prevention of H. pylori‐associated gastric cancer were investigated in Mongolian gerbils. To examine the effects of arctigenin and NDGA on stomach carcinogenesis, specific pathogen‐free male, 5‐week‐old gerbils were infected with H. pylori, administered 10 p.p.m. N‐methyl‐N‐nitrosourea in their drinking water and fed diets containing various concentrations of lignans until they were killed after 52 weeks. At a dietary level of 0.25%, NDGA significantly decreased the incidence of gastric adenocarcinomas. Arctigenin, in contrast, failed to attenuate neoplasia at a level of 0.1%. Both NDGA and arctigenin significantly reduced serum 8‐hydroxy‐2′‐deoxyguanosine levels at doses of 0.25 and 0.05% (NDGA), and 0.1% (arctigenin). Administration of 0.25% NDGA significantly suppressed the formation of intestinal metaplasia both in the antrum and the corpus. Although all three lignans dose‐dependently inhibited the in vitro proliferation of H. pylori, there were no differences in the titers of anti‐H. pylori antibodies or the amount of the H. pylori‐specific urease A gene among all H. pylori‐infected groups. These results suggest that NDGA might be effective for prevention of gastric carcinogenesis. The possible mechanisms appear to be related to inhibitory effects on progression of gastritis and antioxidative activity rather than direct antimicrobial influence. (Cancer Sci 2007; 98: 1689–1695)

β‐Catenin gene alteration in glandular stomach adenocarcinomas in N‐methyl‐N‐nitrosourea‐treated and Helicobacter pylori‐infected Mongolian gerbils

The goal of this study was to elucidate whether β‐catenin gene mutations might contribute to glandular stomach carcinogenesis in Helicobacter pylori (H.pylori)‐infected Mongolian gerbils. Firstly, exon 3 of gerbil β‐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. Pep‐tide 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 β‐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) β‐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 β‐catenin localization (7/7). Analysis of exon 3 of the β‐catenin gene demonstrated all tumors with membrane or cytoplasmic staining as well as surrounding normal mucosa (S) to feature wild‐type β‐catenin. In contrast, the lesion with nuclear staining had a mis‐sense 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 β‐catenin may not be a frequent target for mutation in stomach carcinogenesis in MNU+H. pylori‐treated gerbils.

Coexistence of gastric‐ and intestinal‐type endocrine cells in gastric and intestinal mixed intestinal metaplasia of the human stomach

Intestinal metaplasia (IM) in the human stomach has previously been classified into a gastric and intestinal mixed (GI‐IM) and a solely intestinal phenotype (I‐IM). The phenotypes of mucous and endocrine cells were evaluated in 3034 glandular ducts associated with chronic gastritis. In the pyloric region, the relative expression of gastric endocrine cell markers, such as gastrin and somatostatin, decreased gradually from glandular ducts with only gastric mucous cell phenotype (G type) to GI‐IM toward I‐IM, while that of the intestinal endocrine cell markers, glicentin, gastric inhibitory polypeptide (GIP), and glucagon‐like peptide‐1 (GLP‐1) was inversely correlated. In the fundic region, gastrin‐positive  cells  emerged  in  the  pseudo‐pyloric  and  GI‐IM glands, whereas I‐IM glands did not possess any gastrin‐positive cells, suggesting the presence of a distinct pathway of intestinalization. Double staining revealed coexistence of gastrin‐ and GLP‐1‐positive cells in the same gland and occasionally in the same cell in GI‐IM glands. These results suggest that the phenotypes of endocrine cells are in line with those for mucous counterparts and support the concept that all of the different types of mucous and endocrine cells in normal and IM glands might be derived from a single progenitor cell in each gland.

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

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 Helicobacter pylori infection in the Mongolian gerbil model. The numbers of chromogranin A (CgA)‐positive, gastrin‐positive and gastric inhibitory polypeptide (GIP)‐positive cells in H. pylori‐infected groups was increased significantly compared with the non‐infected case. However, CgA‐positive and gastrin‐positive cells then decreased from 50 through 100 experimental weeks after H. pylori infection, whereas GIP‐positive cells increased. Coexistence of gastrin‐positive and GIP‐positive cells was detected in the same gastric and intestinal mixed phenotypic glandular‐type glands. In conclusion, the endocrine cell phenotype is in line with that of the mucous counterpart in the glands of H. pylori‐infected Mongolian gerbil stomach, supporting the concept that development of intestinal metaplasia is due to the abnormal differentiation of a stem cell. (Cancer Sci 2006; 97: 1015–1022)

Colonic and small-intestinal phenotypes in gastric cancers: Relationships with clinicopathological findings

The clinicopathological significance of colonic and small‐intestinal phenotypes has hitherto remained unclear in gastric cancers. The purpose of the present study was therefore to examine 86 gastric carcinomas histologically and phenotypically using several phenotypic markers, including colon‐specific carbonic anhydrase 1 (CA1) and sucrase as small‐intestine specific marker. Of 86 gastric cancers, sucrase and CA1 expression was observed in 12 (14.0%) and only in two cases (2.3%), respectively, associated with other intestinal markers such as villin and mucin core protein (MUC)2. In the sucrase cases, expression appeared independent of the stage. However, CA1 expression was observed only in two advanced cases. No association was observed between colonic and small‐intestinal phenotypes, and lymph node metastasis and postoperative survival in the advanced gastric cancer cases with intestinal phenotypic expression. Cdx2 appeared to be linked to upregulation of both CA1 and sucrase. In conclusion, the data suggest that colonic phenotype occurs rarely in gastric carcinogenesis. Colonic and small‐intestinal phenotypes appear with expression of several intestinal phenotypic markers under the control of Cdx2 and presumably other related transcription factors.

Efficacy of trastuzumab beyond progression as second-line chemotherapy for HER2-positive advanced gastric cancer

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