Aberrant Expression of CDX2 in the Gastric Mucosa With and Without Intestinal Metaplasia: Effect of Eradication of <i>Helicobacter pylori</i>

Satoh, Kiichi; Mutoh, Hiroyuki; Eda, Akashi; Yanaka, Ichiro; Osawa, Hiroyuki; Honda, Sayaka; Kawata, Hiroshi; Kihira, Ken; Sugano, Kentaro

doi:10.1046/j.1523-5378.2002.00080.x

Cited by 90 publications

(72 citation statements)

References 26 publications

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“…7,13,[15][16][17][18]30 Our results are entirely consistent with these studies in that CDX2 staining was observed in only a subset of gastric cancers and significantly favored the intestinal-type tumors over the diffuse variants.…”

Section: Discussionsupporting

confidence: 91%

“…11,12 In humans, intestinal metaplasia of the stomach and esophagus is consistently accompanied by CDX2 expression. 6,[13][14][15][16] The relationship between CDX2 expression and intestinal differentiation suggests that CDX2 may serve as a specific marker for epithelial neoplasms of the gastrointestinal (GI) tract. This is supported by several recently published surveys in which selective staining of colorectal and duodenal adenocarcinomas has been observed using a commercially available monoclonal antibody to CDX2.…”

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confidence: 99%

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The homeobox intestinal differentiation factor CDX2 is selectively expressed in gastrointestinal adenocarcinomas

et al. 2004

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CDX2 is a homeobox domain-containing transcription factor that is important in the development and differentiation of the intestines. Based on recent studies, CDX2 expression is immunohistochemically detectable in normal colonic enterocytes and is retained in most, but not all, colorectal adenocarcinomas. CDX2 expression has also been documented in a subset of adenocarcinomas arising in the stomach, esophagus and ovary. In this study, we examined CDX2 expression in a series of large tissue microarrays representing 4652 samples of normal and neoplastic tissues. Strong nuclear staining for CDX2 was observed in 97.9% of 140 colonic adenomas, 85.7% of 1109 colonic adenocarcinomas overall and 81.8% of 55 mucinous variants. There was no significant difference in the staining of well-differentiated (96%) and moderately differentiated tumors (90.8%, P ¼ 0.18), but poorly differentiated tumors showed reduced overall expression (56.0%, Po0.000001). Correspondingly, there was an inverse correlation between CDX2 expression and tumor stage, with a significant decrease in staining between pT2 and pT3 tumors (95.8 vs 89.0%, Po0.012), and between pT3 and pT4 tumors (89.0 vs 79.8%, Po0.016). Analysis of 140 locally advanced, CDX2-positive colorectal adenocarcinomas coarrayed with their matching lymph node metastases revealed that expression of this marker was retained in 82.1% of the metastases. Consistent with previous reports, CDX2 staining was observed in gastric adenocarcinomas (n ¼ 71), more commonly in the intestinal-type than the diffuse-type (28.9 vs 11.5%, Po0.05). Occasional ovarian carcinomas were positive for CDX2, including mucinous (10.5%), endometrioid (9.3%) and serous variants (2%), but expression was either very rare or absent in primary carcinomas of the lung, breast, thyroid, pancreas, liver, gallbladder, kidney, endometrium and urinary bladder. A low frequency of CDX2 expression in pancreatic and biliary carcinomas observed on the microarrays was pursued further by comparing these tumors with ampullary adenocarcinomas on conventional sections. Ampullary adenocarcinomas were more commonly positive for CDX2 (19/24, 79%) than cholangiocarcinomas (1/11, 9%) and pancreatic carcinomas (3/20, 15%). In summary, CDX2 is a sensitive and specific marker for colorectal adenocarcinoma, although its expression is decreased among higher grade and stage tumors, and it is not invariably present in metastases from positive primaries. CDX2 may also be helpful in distinguishing adenocarcinomas of the ampulla from those arising in the pancreas and biliary tree.

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Section: Discussionsupporting

confidence: 91%

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confidence: 99%

The homeobox intestinal differentiation factor CDX2 is selectively expressed in gastrointestinal adenocarcinomas

et al. 2004

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“…24,35 The involvement of TLR2 and/or TLR4 in Helicobacter pylori infections has been revealed in cultured gastric epithelial cell lines, 33,34 in which MUC2 was induced to express by TLR2/ bacterial components and the activation of NF-kB. 3,31,32 PAMPs-induced CDX2 and MUC2 overexpression via an NF-kB pathway located downstream of TLRs. This study showed that pretreatment of BECs with MG132 reduced the CDX2 and MUC2 mRNA upregulation induced by LPS, suggesting that upregulation of the CDX2 and MUC2 pathway by PAMPs was related to the activation of TLR2/ TLR4 with the translocation of NF-kB.…”

Section: Intestinal Metaplasia Of Bile Ducts H Ikeda Et Almentioning

confidence: 99%

“…Sixteen types of MUC have been identified. Intestinal metaplasia associated with the aberrant expression of MUC2 [1][2][3][4] is reportedly involved in tumorigenesis in several organs. Recent studies revealed that CDX2, a caudalrelated homeobox gene encoding an intestine-specific transcription factor, is a regulatory factor of intestinal development and expression of intestinal genes including MUC2 and is involved in intestinal metaplasia.…”

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confidence: 99%

Interaction of Toll-like receptors with bacterial components induces expression of CDX2 and MUC2 in rat biliary epithelium in vivo and in culture

Ikeda

Sasaki

Ishikawa

et al. 2007

Laboratory Investigation

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The mechanism of transformation of biliary epithelium leading to intestinal metaplasia, which is significantly involved in biliary diseases, remains unclear. CDX2, an intestine-specific transcription factor, is thought to regulate intestinal mucin MUC2 (mucus core protein) expression. We took advantage of polycystic kidney (PCK) rats as a model of chronic suppurative cholangitis with intestinal metaplasia and of cultured biliary epithelial cells (BECs) from PCK rats to clarify the causal relation between bacterial components such as pathogen-associated molecular patterns (PAMPs) and the development of intestinal metaplasia of bile ducts. Histological, immunohistochemical, and in situ hybridization studies were conducted in PCK rat livers. In cultured BECs, CDX2 and MUC2 were expressed following treatment with PAMPs and inhibitors (anti-Toll-like receptor (TLR)2/TLR4 antibody, nuclear factor-kB (NF-kB) inhibitor MG132). Chronic suppurative cholangitis with intestinal metaplasia developed as the PCK rats aged, and intestinal metaplasia and aberrant CDX2 and MUC2 expression developed in parallel. Intraluminal bacteria and the expression of TLR2 and TLR4 in BECs were demonstrated in the bile ducts, showing chronic suppurative cholangitis. In cultured BECs, treatment with PAMPs induced upregulation of CDX2 and MUC2 expression, and this effect was abolished by pretreatment with anti-TLR2 and anti-TLR4 antibody and MG132. A knockdown of CDX2 by CDX2 small interfering RNA inhibited MUC2 expression in cultured BECs induced by PAMPs, and transfection of CDX2 expression vector induced MUC2 expression. In conclusion, bacterial components may induce upregulation of the CDX2 expression followed by MUC2 expression via TLR and the NF-kB system in cultured BECs, and could be related to the development of intestinal metaplasia of the bile ducts. Intestinal metaplasia associated with the aberrant expression of MUC2 1-4 is reportedly involved in tumorigenesis in several organs. Recent studies revealed that CDX2, a caudalrelated homeobox gene encoding an intestine-specific transcription factor, is a regulatory factor of intestinal development and expression of intestinal genes including MUC2 and is involved in intestinal metaplasia. 2,4,5-8 CDX2-dependent intestinal metaplasia is noted in Barrett's esophagus with MUC2 expression, and bile acid and chronic acid exposure have been reported to induce CDX2 expression. 2,[4][5][6]8,9 Intestinal metaplasia is also involved in the pathogenesis of biliary diseases. For example, in chronic cholangitis such as hepatolithiasis, intestinal metaplasia with goblet cells occurs, and MUC2 is aberrantly expressed in goblet cells colocalized with CDX2.

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“…In two separate mouse models, ectopic expression of CDX2 in the stomach induced gastric intestinal metaplasia Silberg et al, 2002). In humans, CDX2 is not expressed in normal gastric cells but is prominently expressed in gastric intestinal metaplasia, consistent with its putative role in the induction of gastric intestinal metaplasia (Bai et al, 2002;Eda et al, 2002;Satoh et al, 2002;Almeida et al, 2003;Mizoshita et al, 2004b;Tsukamoto et al, 2004).…”

Section: Introductionmentioning

confidence: 83%

CDX2 does not suppress tumorigenicity in the human gastric cancer cell line MKN45

et al. 2005

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CDX2 is a Drosophila caudal-related homeobox transcription factor that is expressed specifically in the intestine. In mice, ectopic expression of CDX2 in the gastric mucosa gives rise to intestinal metaplasia and in one model, gastric carcinoma. In humans, increased CDX2 expression is associated with gastric intestinal metaplasia and tubular adenocarcinomas. These patterns of expression have shown that CDX2 is important for the initiation of intestinal metaplasia in the gastric mucosa, but the role of CDX2 in established gastric cancer remains unclear. We sought to determine whether CDX2 contributes to tumorigenic potential in established gastric cancer. The CDX2 gene in MKN45 gastric carcinoma cells was disrupted using targeted homologous recombination. The resulting CDX2 À/À cells are essentially identical to their parental cells, with the exception of CDX2 ablation. We found no significant differences in the proliferation of CDX2 À/À cells compared to CDX2þ / þ cells, in vitro or in vivo. Molecular analyses show that loss of CDX2 predominantly altered the expression of genes involved in intestinal glandular differentiation and adhesion. However, there were no microscopic differences in tumor differentiation. We conclude that disruption of CDX2 in MKN45 cells does not significantly affect their tumorigenic potential.

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Aberrant Expression of CDX2 in the Gastric Mucosa With and Without Intestinal Metaplasia: Effect of Eradication of Helicobacter pylori

Abstract: Our results indicate that CDX2 expression in the gastric mucosa is found in patients with chronic gastritis and is closely associated with IM. CDX2 expression in IM or the gastric epithelial cells did not disappear after eradication of H. pylori.

Cited by 90 publications

References 26 publications

The homeobox intestinal differentiation factor CDX2 is selectively expressed in gastrointestinal adenocarcinomas

The homeobox intestinal differentiation factor CDX2 is selectively expressed in gastrointestinal adenocarcinomas

Interaction of Toll-like receptors with bacterial components induces expression of CDX2 and MUC2 in rat biliary epithelium in vivo and in culture

CDX2 does not suppress tumorigenicity in the human gastric cancer cell line MKN45

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