Metaplasia Of Stomach Research Articles

A signalling cascade of IL-33 to IL-13 regulates metaplasia in the mouse stomach

ObjectiveAlternatively activated macrophages (M2) are associated with the progression of spasmolytic polypeptide-expressing metaplasia (SPEM) in the stomach. However, the precise mechanism(s) and critical mediators that induce SPEM are unknown.DesignTo determine...

Targeted Apoptosis of Parietal Cells Is Insufficient to Induce Metaplasia in Stomach

Parietal cell atrophy is considered to cause metaplasia in the stomach. We developed mice that express the diphtheria toxin receptor specifically in parietal cells to induce their death, and found this to increase proliferation in the normal stem cell zone and neck but not to cause metaplastic reprogramming of chief cells. Furthermore, the metaplasia-inducing agents tamoxifen or DMP-777 still induced metaplasia even after previous destruction of parietal cells by diphtheria toxin. Atrophy of parietal cells alone therefore is not sufficient to induce metaplasia: completion of metaplastic reprogramming of chief cells requires mechanisms beyond parietal cell injury or death.

A Role for the Vacuolating Cytotoxin, VacA, in Colonization and Helicobacter pylori–Induced Metaplasia in the Stomach

Carriage of Helicobacter pylori strains producing more active (s1/i1) forms of VacA is strongly associated with gastric adenocarcinoma. To our knowledge, we are the first to determine effects of different polymorphic forms of VacA on inflammation and metaplasia in the mouse stomach. Bacteria producing the less active s2/i2 form of VacA colonized mice more efficiently than mutants null for VacA or producing more active forms of it, providing the first evidence of a positive role for the minimally active s2/i2 toxin. Strains producing more active toxin forms induced more severe and extensive metaplasia and inflammation in the mouse stomach than strains producing weakly active (s2/i2) toxin. We also examined the association in humans, controlling for cagPAI status. In human gastric biopsy specimens, the vacA i1 allele was strongly associated with precancerous intestinal metaplasia, with almost complete absence of intestinal metaplasia in subjects infected with i2-type strains, even in a vacA s1, cagA+ background.

58 Biomarkers of Human Stomach Metaplasia Progression Revealed by Proteomic Profiling of Paraffin-Embedded Tissues

Background: Trefoil factor 1 protein (TFF1) is a small secreted protein. It is constitutively and strongly expressed in the stomach, where it has a key role in maintaining mucosal integrity. Our previous studies using TFF1-knockout mice indicated a mucosal pro-inflammatory phenotype with a sequence of morphological and signaling changes leading to the development of gastric cancer. Methods and Results: In the current study, we hypothesized that the tumorigenic phenotype obtained in the TFF1-deficient gastric tissues is induced through regulation of b-catenin/TCF pathway. Using immunohistochemistry for b-catenin expression in the pyloric antrum region of the stomach in TFF1 wild type and TFF1 knockout mice, our results showed strong nuclear accumulation of b-catenin in the epithelial cells of TFF1 knockout mice; this accumulation was absent in TFF1 wild type. Using In Vitro cell models, we investigated the transcriptional regulation of b-catenin/TCF activity by TFF1 using the pTOP flash and its mutant pFOP flash luciferase reporter assays. MKN28 and SNU1 TFF1 stable cell lines showed 80% and 50% decrease in b-catenin activity, respectively, as compared to their corresponding pcDNA control cells (P<0.001). These results were confirmed using TFF1 adenovirus system inMKN28 cell line where transient TFF1 expression decreased b-catenin/TCF luciferase activity by 60% relative to control (P<0.01). Using quantitative real time PCR, we found that stable TFF1 expression led to a significant downregulation of b-catenin/TCF target genes, c-Myc and Cyclin D1 in MKN28 and SNU1 cell lines, as compared to their pcDNA control cells (P<.01). The immunofluorescence assay data indicated that reconstitution of TFF1 expression in MKN28 cell line by TFF1 adenovirus (5MOI) abrogated translocation of b-catenin to the nucleus and induced strong staining in the cell membrane as compared to the control cells where the b-catenin showed a strong staining in the nucleus. Conclusion: Our data suggest that b-catenin activation could play a role in the development of gastric neoplasms in TFF1 knockout mice. In addition, our In Vitro and In Vivo studies unveil a novel mechanism by which TFF1 regulates b-catenin/TCF activity, thereby implicating its tumor suppressor function in gastric cancer. Ongoing studies using In Vivo, ex-vivo and In Vitromodels are underway to dissect the regulatory mechanisms that mediate TFF1 suppression of b-catenin/TCF.

Abstract 1325: Loss of AGR2 results in compromised chief cell differentiation and preneoplastic metaplasia of stomach

Abstract Background: AGR2 represents Anterior Gradient 2, initially discovered in Xenopus where its expression at the anterior pole of the developing embryo induces forebrain and cement gland formation. In salamanders, AGR2 plays a role in nerve-dependent limb regeneration. AGR2 induces foci formation and anchorage independent growth in vitro. Increased AGR2 is observed in adenocarcinoma of the prostate, breast, pancreas, esophagus and ovaries. AGR2 overexpression transforms NIH3T3 cells resulting into tumor xenografts in nude mice. AGR2 induces expression of amphiregullin, EGFR ligand by affecting Hippo signaling pathway. In normal tissues it is expressed in the secretory lineage, paneth, enteroendocrine and goblet cells of the small intestine. AGR2's expression and role in stomach development and disease has not been studied. Stomach consists of three main regions: the fundus, lined with squamous keratinized epithelium, the corpus and the pylorus (glandular stomach). The corpus glands consist of the parietal cells, chief cells, foveolar cells, enterochromaffin cells, neck cells and stem cells. Parietal cells secrete acid for digestion, chief cells make digestive enzyme, pepsinogen and the foveolar cells secrete mucus. Proposed functions of neck cells include a role in mucus secretion or as a progenitor for chief cells. AGR2 is expressed by neck cells in the normal stomach. Hypothesis and methods: AGR2 expression in neck cells is critical for normal development of the stomach. This hypothesis is tested by generating a conditional AGR2 knock out mouse in which the floxed exons are excised with CMV induced expression of Cre-recombinase. Immunohistochemisty with lineage specific antibodies was performed to analyze the phenotype. Results: AGR2 loss results in weight loss and enlarged stomach in the mice. Histological analysis of stomach from AGR2 knock out mice demonstrates that AGR2 expression in the mucus neck cells is dispensable to terminal differentiation of chief cells. Loss of AGR2 results in incomplete maturation of chief cells. AGR2 loss is accompanied with increased cell proliferation in the stomach compared to the litter mate controls. The dividing cells exclude the lineage markers: H-KATPase (parietal cells), Muc5AC (faveolar cells), and intrinsic factor (chief cells). A significant expansion of TFF2 positive cells is observed that is also referred to as Spasmolytic polypeptide-expressing metaplasia (SPEM). In humans, SPEM is associated with precancerous stomach and is observed upon parietal cell loss.TFF2 in the normal stomach is expressed in the neck cells. Previous studies show that loss of parietal cells results in SPEM in the stomach. Loss of AGR2 triggers expansion of TFF2 expressing cells/SPEM before the loss of parietal cells. Conclusions: • AGR2 expression in neck cells is critical for terminal differentiation of chief cells. • Loss of AGR2 results in hyperplasia and SPEM in the stomach Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1325. doi:1538-7445.AM2012-1325

CDX2-regulated expression of iron transport protein hephaestin in intestinal and colonic epithelium

The homeobox transcription factor CDX2 has a key role in intestinal development and differentiation. Mice heterozygous for Cdx2 inactivation develop colonic polyps with epithelial cells showing gastric or squamous differentiation. Loss of CDX2 expression is seen in some poorly differentiated colon carcinomas in humans. Conversely, ectopic CDX2 expression in the stomach of transgenic mice promotes intestinal metaplasia, and CDX2 expression often is seen in intestinal metaplasia in stomach and esophagus. To enhance knowledge of CDX2 function, we sought to define CDX2-regulated genes. HT-29 and WiDr colorectal cancer (CRC) cells with low endogenous CDX2 expression were transduced with a CDX2 expression vector, and gene expression changes were assessed by microarrays. The gene for ceruloplasmin-related iron transport protein hephaestin (HEPH) was induced by CDX2 in HT-29 and WiDr. In other CRC lines and human and mice tissues, endogenous HEPH expression was linked to CDX2 expression. Activation of CDX2 rapidly induced HEPH expression, and RNA interference-mediated inhibition of CDX2 led to lower HEPH expression. Studies with HEPH reporter gene constructs and chromatin-immunoprecipitation approaches suggested that CDX2 directly regulates HEPH transcription. In CRC cells, CDX2 induction suppressed intracellular iron levels, consistent with the view that HEPH regulates iron export. CDX2 expression was modulated in response to changes in intracellular iron levels, implying a regulatory pathway in which increased iron levels lead to increased expression of CDX2 and HEPH and enhanced iron export. CDX2 has a key role in regulating HEPH expression and iron levels in intestinal cells.

A prospective clinical study to know the relationship between Helicobacter pylori infection and telomerase activity in intestinal metaplasia of stomach

A prospective clinical study to know the relationship between Helicobacter pylori infection and telomerase activity in intestinal metaplasia of stomach

Villin, intestinal brush border hydrolases and keratin polypeptides in intestinal metaplasia and gastric cancer; an immunohistologic study emphasizing the different degrees of intestinal and gastric differentiation in signet ring cell carcinomas

Gastric carcinomas have been assayed for the presence of villin and for the small intestinal hydrolases aminopeptidase N and sucrase isomaltase. These proteins seem not to be present in normal stomach epithelium. However intestinal metaplasia in stomach, and tumour cells in the glandular patterns of gastric carcinoma were positive for all three markers, showing characteristic apical positivity. In contrast, in diffuse gastric carcinomas the percentage of signet ring cells positive for these markers varied from 10-100% with each marker showing a similar percentage of positive cells. Testing of gastric carcinomas with antibodies specific for different keratin polypeptides showed that while all 7 tumours were positive for keratins 8 and 18.2 were also positive for keratin 7. In the keratin 7 positive tumours all tumour cells were keratin 7 positive. The keratin 8 antibody also reacted on routinely fixed specimens. Thus gastric carcinomas reveal different degrees of gastric and intestinal differentiation.