CDX2 expression in the stomach with intestinal metaplasia and intestinal-type cancer: Prognostic implications

Seno, Hiroshi; Oshima, Masanobu; Taniguchi, Masashi; Usami, Kazuo; Ishikawa, Tomo-o; Chiba, Tomohiro; Taketo, Matsubara

doi:10.3892/ijo.21.4.769

Cited by 77 publications

(97 citation statements)

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“…Overexpression of COX-2 and overproduction of PGE 2 have been shown to regulate tumor angiogenesis, and the EP2 receptor has been implicated in this process Tsujii et al, 1998;Rozic et al, 2001;Sonoshita et al, 2001;Dormond et al, 2002;Seno et al, 2002). However, the molecular mechanisms remain to be elucidated and, most importantly, it is not clear whether EP2 signaling in endothelium directly contributes to tumor angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it has been shown that activation of EP2 via PGE 2 contributes to mammary hyperplasia by enhancing the expression of amphiregulin, a potent mammary epithelial cell growth factor (Chang et al, 2005). Moreover, studies have shown that COX-2 and PGE 2 regulate tumor angiogenesis (Tsujii et al, 1998;Rozic et al, 2001;Sonoshita et al, 2001;Seno et al, 2002;Kuwano et al, 2004). Homozygous deletion of the gene encoding EP2 decreases the number and size of intestinal polyps in Apc D716 mice, a mouse model for human familial adenomatous polyposis (Sonoshita et al, 2001;Seno et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, studies have shown that COX-2 and PGE 2 regulate tumor angiogenesis (Tsujii et al, 1998;Rozic et al, 2001;Sonoshita et al, 2001;Seno et al, 2002;Kuwano et al, 2004). Homozygous deletion of the gene encoding EP2 decreases the number and size of intestinal polyps in Apc D716 mice, a mouse model for human familial adenomatous polyposis (Sonoshita et al, 2001;Seno et al, 2002). These tumors exhibit reduced tumor vascular density, suggesting that the reduced tumor growth in the EP2 knockout mice is owing to the inhibition of tumor angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

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EP2, a receptor for PGE2, regulates tumor angiogenesis through direct effects on endothelial cell motility and survival

et al. 2006

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Prostaglandin E2 (PGE 2 ), a major cyclooxygenase (COX) metabolite, plays important roles in tumor biology. We studied the role of EP2, a receptor for PGE 2 , in tumor angiogenesis using EP2 knockout mice. We found that deletion of the EP2 receptor impaired tumor angiogenesis and this finding was confirmed by an in vivo corneal angiogenesis model and an ex vivo aortic ring assay. To further characterize the cellular mechanisms of the EP2 receptor in angiogenesis, we isolated primary pulmonary endothelial cells (ECs) from wild-type (wt) and EP2 À/À mice and observed that EP2 À/À ECs exhibited defects in vascular branch formation when compared to wt ECs. In addition, EP2 À/À ECs showed impaired cell motility on collagen-coated surface and they responded poorly to PGE 2 -induced cell migration compared to control cells. However, no difference in cell proliferation was observed between the EP2 À/À and wt Ecs. In addition, EP2 À/À ECs were more susceptible to apoptosis than wt cells under growth factor depletion conditions. Collectively, our data demonstrate that EP2 signaling in endothelium directly regulates tumor angiogenesis by contributing to cell survival and endothelial cell motility. Moreover, our finding suggests that EP2 is a major receptor in PGE 2 -mediated cell motility in ECs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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EP2, a receptor for PGE2, regulates tumor angiogenesis through direct effects on endothelial cell motility and survival

et al. 2006

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“…Determination of ABI Anaphase bridges were scored as described previously (Seno et al, 2002;Aoki et al, 2003;Mizoshita et al, 2003;Supplementary Information).…”

Section: Immunohistochemical Analysesmentioning

confidence: 99%

Chromosomal instability by β-catenin/TCF transcription in APC or β-catenin mutant cells

Aoki

Sugai

et al. 2006

Oncogene

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Adenomatous polyposis coli (APC/Apc) gene encodes a key tumor suppressor whose mutations activate b-catenin/ T-cell factor (TCF)-mediated transcription (canonical Wnt signaling). Here, we show that Wnt signaling can cause chromosomal instability (CIN). As an indicator of CIN, we scored anaphase bridge index (ABI) in mouse polyps and ES cells where Wnt signaling was activated by Apc or b-catenin mutations. We found three to nine times higher ABI than in wild-type controls. Furthermore, karyotype analysis confirmed that the Wnt signalactivated ES cells produced new chromosomal aberrations at higher rates; hence CIN. Consistently, expression of dominant-negative TCFs in these cells reduced their ABI. We also found that Wnt signal activation increased phosphorylation of Cdc2 (Cdk1) that inhibited its activity, and suppressed apoptosis upon exposure of the cells to nocodazole or colcemid. The data suggest that Wnt signaling stimulates the cells to escape from mitotic arrest and apoptosis, resulting in CIN. In human gastric cancer tissues with nuclear b-catenin, ABI was significantly higher than in those without. These results collectively indicate that b-catenin/TCF-mediated transcription itself increases CIN through dysregulation of G2/M progression.

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“…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%

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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CDX2 expression in the stomach with intestinal metaplasia and intestinal-type cancer: Prognostic implications

Cited by 77 publications

References 0 publications

EP2, a receptor for PGE2, regulates tumor angiogenesis through direct effects on endothelial cell motility and survival

EP2, a receptor for PGE2, regulates tumor angiogenesis through direct effects on endothelial cell motility and survival

Chromosomal instability by β-catenin/TCF transcription in APC or β-catenin mutant cells

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

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