found that gastric carcinomas could be broadly divided into gland-forming adenocarcinomas and poorly differentiated carcinomas, which included signet-ring cell carcinomas. The former were found to retain intestinal features, and the latter tended to disclose a diffusely infiltrative growth pattern; Laurén referred to these as intestinal-type and diffuse-type, respectively, reporting that 53% of his samples were intestinal-type, 33% were diffuse-type, and the remaining 14% were unclassifiable [1].In the differentiated adenocarcinomas, intestinal metaplasia was often seen in the stomach, and intestinaltype cancers were thought to arise from the intestinal metaplasia. On the other hand, diffuse-type cancers did not retain intestinal characteristics, and they were considered to arise in the ordinary gastric mucosa, which was not involved in intestinal metaplasia [2,3]. In the middle of the 1980s, Helicobacter pylori was found to cause chronic active gastritis, and it was suggested that H. pylori played an important role in gastric carcinogenesis. In this respect, a hypothesis was that H. pylori caused chronic active gastritis with intestinal metaplasia, resulting in the development of intestinal-type adenocarcinomas [4,5].However, several studies appeared which described well-differentiated adenocarcinomas arising in nonintestinalized gastric mucosa, and there has been a question whether well-differentiated adenocarcinomas of the stomach were exclusively intestinal type. The recent discovery of MUC genes coding core proteins of mucin has identified the phenotypic expression of gastrointestinal neoplasms [6][7][8]. The disease entity of "gastric-type well-differentiated adenocarcinoma" has recently been accepted, especially in Japan and Europe. This entity has often been a clinicopathological subject of discussion, especially in Japanese journals, because its biological behavior is possibly highly malignant, in spite of the difficulty of making endoscopic and histopathological diagnoses [9,10]. AbstractSince 1985, when gastric-type well-differentiated adenocarcinomas were demonstrated in hyperplastic polyps of the stomach, we have studied phenotypic expression in gastrointestinal epithelial lesions. The recent discovery of MUC genes coding core proteins of mucin has improved research on the phenotypic expression of gastrointestinal neoplasms. The disease entity of gastric-type well-differentiated adenocarcinoma has recently been accepted, especially in Japan and Europe. This entity has often become a clinicopathological subject of discussion, because its biological behavior is possibly highly malignant, in spite of the difficulty in making endoscopic and histopathological diagnoses. Even under these circumstances, the term "gastric adenoma" usually means flat adenoma of the intestinal type. Gastric-type adenomas have been regarded as exceptional until recently. Although gastric-type adenomas could theoretically be classified into foveolar type and pyloric-gland type, foveolar-type adenoma is, in practice, difficult t...

A pyloric gland adenoma (PGA) of the stomach was first described in a book chapter in 1976 by Kurt Elster and has been rarely reported in the literature. We expanded the current immunohistochemical data of these adenomas in a detailed series to further analyse the immunhistochemical status of PGA. From 60 patients with PGA with and without adenocarcinomas of the gastrointestinal tract, an immunhistochemical panel of Mucin 2, Mucin 5AC, Mucin 6, CD10, Ki67 and p53 was used to define the expression of these markers. All PGA were positive for Mucin 6 (deep mucoid glands), which they express over the whole lesion up to the surface. Mucin 5AC expression varies from case to case. A transition from gastric to intestinal differentiation can be observed focally as depicted by Mucin 2 and CD10 in 65% of the cases. The gastric corpus mucosa of elderly patients with either Helicobacter pylori gastritis or autoimmune gastritis is highly affected. Almost 47% of all PGA already underwent malignant transformation into adenocarcinoma. Significant immunohistochemical differences could be detected between PGA with and without adenocarcinoma regarding ki67 and p53. The diagnosis of PGA can be confirmed immunohistochemically by staining against apomucin 6 and apomucin 5AC. Focal intestinal differentiation supports the hypothesis that gastric adenocarcinomas can initially develop from carcinomas of the gastric type and transform into intestinal type later on. The high frequency of malignant transformation of PGA underlines its high potential for invasive malignancy.

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Several epidemiological cohort studies have suggested that duodeno-gastroesophageal reflux per se induces Barrett's esophagus leading to increased risk of the development of esophageal adenocarcinoma (EAC). However, the exact causative factors behind EAC remain unclear. Recently, we designed a new duodenal contents reflux model which retained normal stomach function. In this model, duodenal contents flowed back into the esophagus and stomach resulting in repeated re-entry into the esophagus through the site of esophagojejunostomy. To elucidate the factors underlying the development of EAC, thiazolidine-4-carboxylic acid (thioproline, TPRO) was applied to the new reflux models as a nitrite scavenger and as a probe to detect reactive nitrogen species (RNS). Post-operatively, 31 animals were divided into two groups according to diet. Animals belonging to the control group were given normal diet (n = 18), while the TPRO group was given food containing 0.5% TPRO (n = 13). All esophageal sections in both groups were examined using hematoxylin and eosin staining and immunohistochemical analysis of inducible nitric oxide synthase (iNOS). EACs developed in 7 of 18 rats (38.9%) of the control group, whereas no EACs were detected in the TPRO group (Fisher's exact test, P < 0.05). Conversely, esophageal squamous cell carcinoma (ESCC) was detected in 1 of 18 rats (5.6%) of the control group and in 1 of 13 rats (7.7%) of the TPRO group. The incidence of ESCC was not significantly different between the two groups (P = 0.671). iNOS protein was overexpressed in Barrett's esophagus of both groups. The present results suggest that RNS such as nitric oxide and peroxynitrite and nitroso compounds derived from reflux of duodenal contents play an important role in the development of EAC, and that the primary causes of ESCC and EAC may differ.

Long-term PPI administration promotes development of adenocarcinoma, which is associated with the progression of atrophic corpus gastritis in MGs infected with H pylori.

The dietary components responsible for the development of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) remain unclear. Wistar rats were divided into four groups based on their diet: a low soybean-oil diet, a low cow-fat diet, a high soybean-oil diet, and a high cow-fat diet. First, we evaluated the bile acid composition of the bile juice in each group without operation, using high-performance liquid chromatography. Because only high cowfat intake induced changes in the composition of bile acids in bile juice, we then selected animals fed with a low soybean-oil diet and those with a high cow-fat diet to carry out esophago-jejunostomy for reflux of the duodenal contents, and compared sequential morphological changes between these groups up to 30 weeks after surgery. At 30 weeks after surgery, the reflux animals in the high cow-fat group showed a significantly higher incidence of BE and Barrett's dysplasia than those in the low soybean-oil group, and the incidence of EAC in the high cow-fat group was also slightly higher than that in the low soybean-oil group. High dietary animal fat changed the bile-acid composition and increased the concentration of taurine conjugates in the bile juice. These increased bile acids promoted the development of BE and Barrett's dysplasia leading to EAC. (Cancer Sci 2007; 98: [1683][1684][1685][1686][1687][1688]

Gastric cancer can be classified as cardia and non-cardia subtypes according to the anatomic site. Although the gastric cancer incidence has decreased steadily in several countries over the past 50 years, the incidence of cardia cancers and esophageal adenocarcinoma (EAC) continue to increase. The etiological factors involved in the development of both cardia cancers and EACs are associated with high animal fat intake, which causes severe obesity. Central obesity plays roles in cardiac-type mucosa lengthening and partial hiatus hernia development. There are two distinct etiologies of cardia cancer subtypes: one associated with gastroesophageal reflux (GER), which predominantly occurs in patients without Helicobacter pylori (H. pylori) infection and resembles EAC, and the other associated with H. pylori atrophic gastritis, which resembles non-cardia cancer. The former can be developed in the environment of high volume duodenal content reflux, including bile acids and a higher acid production in H. pylori–negative patients. N-nitroso compounds, which are generated from the refluxate that includes a large volume of bile acids and are stabilized in the stomach (which has high levels of gastric acid), play a pivotal role in this carcinogenesis. The latter can be associated with the changing colonization of H. pylori from the distal to the proximal stomach with atrophic gastritis because a high concentration of soluble bile acids in an environment of low acid production is likely to act as a bactericide or chemorepellent for H. pylori in the distal stomach. The manuscript introduces new insights in causative factors of adenocarcinoma of the cardia about the role of bile acids in gastro-esophageal refluxate based upon robust evidences supporting interactions among pH, H. pylori, and bile acids.

BackgroundEzrin is a member of the ezrin, radixin, and moesin family that provides a functional link between the plasma membrane and the cortical actin cytoskeleton. A correlation between ezrin overexpression and aggressive cancer behavior has been recently reported in various tumor types. However, its roles in the mechanisms underlying progression of tongue squamous cell carcinoma (SCC) are unclear.MethodWe used human tongue SCC and noncancerous tissue microarrays to immunohistochemically analyze the ezrin expression level and its relationship with proliferative activity. The human tongue SCC cell line HSC-3 was used to determine the effects of ezrin RNA interference (RNAi) on cancer cells during MTT; wound healing and invasion assays; immunofluorescence of the actin cytoskeleton; and western blotting of E-cadherin, N-cadherin, β-catenin, and the active and total RhoA/Rac1/cdc42.ResultsEzrin was overexpressed in 46.4% of the tumors examined in human tongue SCC tissue microarrays. Ezrin expression was correlated with the Ki-67 index. Ezrin depletion by RNAi in the HSC-3 cells significantly reduced cell proliferation, migration, and invasiveness and disturbed actin reorganization during podia formation. Its effects on RhoA/Rac1/cdc42 expression were not significant, whereas it enhanced E-cadherin and β-catenin expression and decreased N-cadherin expression.ConclusionsEzrin is often overexpressed in primary tongue SCCs and may have an important role in their growth, migration, and invasiveness possibly via its relationship with the E-cadherin/β-catenin complex and the cadherin switch. Thus, ezrin could be a therapeutic target in tongue SCC.