Aberrant expression of CDX2 is closely related to the intestinal metaplasia and MUC2 expression in intraductal papillary neoplasm of the liver in hepatolithiasis

Ishikawa, Akira; Sasaki, Motoko; Ohira, Susumu; Ohta, Tetsuo; Oda, Koji; Nimura, Yuji; Chen, Miin‐Fu; Jan, Yi-Yin; Yeh, Ta‐Sen; Nakanuma, Yasuni

doi:10.1038/labinvest.3700087

Cited by 75 publications

(60 citation statements)

References 36 publications

(68 reference statements)

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“…In particular, MUC2 is specific to intestinal goblet cells (Velcich et al, 2002;Sonoda et al, 2004). Previous studies have shown that CDX2 transcriptionally regulates the MUC2 gene in MKN45 gastric cancer cells (Mesquita et al, 2003;Yamamoto et al, 2003;Ishikawa et al, 2004). We found that loss of CDX2 resulted in loss of MUC2 transcripts, consistent with the notion that CDX2 is important for maintenance of MUC2 expression (Figure 4c).…”

Section: Cdx2 Does Not Suppress Tumorigenicity In Mkn45 Cells Lh Dangsupporting

confidence: 90%

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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Section: Cdx2 Does Not Suppress Tumorigenicity In Mkn45 Cells Lh Dangsupporting

confidence: 90%

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

et al. 2005

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“…16 After that, great attention was drawn to IPN-B as a biliary counterpart of IPMN-P. [18][19][20]25 The clinicopathological characteristics of IPN-B can be summarized as follows: 16,19,20,26 (1) prominent intraductal papillary proliferation with local dilatation of the bile duct, (2) the acquisition of gastro-intestinal phenotypes, such as MUC2, MUC5AC and CDX2 expressions, (3) mucin hypersecretion, (4) a common association with invasive mucinous carcinoma and (5) favorable prognosis compared to conventional cholangiocarcinoma. Biliary cystic tumors examined in this study shared all of these pathological characteristics.…”

Section: Discussionmentioning

confidence: 99%

Biliary cystic tumors with bile duct communication: a cystic variant of intraductal papillary neoplasm of the bile duct

et al. 2006

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Biliary cystic tumors, which are also called biliary cystadenoma and cystadenocarcinoma, are thought to be a heterogeneous disease entity, and some of them are known to show a luminal communication to the bile duct. In this study, we examined the clinicopathological features of nine cases of biliary cystic tumors with bile duct communication. They were composed of five males and four females with an average age of 67 years (52-84 years). They were multilocular (eight cases) or unilocular (one case), and all cases contained mucinous fluid. A direct luminal communication with the bile ducts was identified in five cases on preoperative or intraoperative cholangiographies. Biliary cystic tumors examined in this study were histologically adenoma (one case), adenocarcinoma in situ (six cases), and adenocarcinoma associated with microinvasive mucinous carcinoma (two cases). One case of adenocarcinoma in situ also had the adenoma component (adenocarcinoma in adenoma). Dysplastic mucinous epithelium proliferated in flat, micropapillary and papillary fashions within the intracystic spaces. Intraepithelial neoplasm was observed within non-dilated adjacent bile ducts, suggesting a direct luminal communication between the cystic tumors and the bile duct. Ovarian-like stroma was not observed in their walls in any cases. Immunohistochemically, seven cases expressed MUC1 or MUC2 in the neoplastic biliary epithelium. All cases except one were alive without any evidences of tumor recurrence after total excision (3-156 months after surgery). These clinicopathological features resembled those of intraductal papillary neoplasm of the bile duct, which had been reported as a biliary counterpart of pancreatic intraductal papillary mucinous neoplasm. In conclusion, biliary cystic tumors with bile duct communication could be regarded as intraductal papillary neoplasm with a prominent cystic dilatation of the bile duct and mucin retention, rather than true biliary cystic neoplasms.

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“…The detailed procedures of the double staining technique have been described elsewhere. 10,11 Tissue from an intraductal papillary mucinous tumor of the pancreas served as positive controls. No positive staining occurred when primary monoclonal antibody was omitted or was replaced by nor-mal mouse serum in negative controls for the staining procedures.…”

Section: Methodsmentioning

confidence: 99%

Characterization of intrahepatic cholangiocarcinoma of the intraductal growth-type and its precursor lesions

et al. 2005

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A cohort of patients with intraductal growth-type intrahepatic cholangiocarcinoma (IG-ICC) and its precursor lesions, collectively termed intraductal papillary neoplasm of the liver (IPNL), was characterized with respect to demographics, clinical manifestations, perioperative management, long-term survival, and molecular features associated with carcinogenesis. A total of 122 patients with IPNL types 1 through 4, 108 patients with non-IG-ICC and 210 patients with hepatolithiasis alone were studied. Expression of CDX2, TFF1, MUC1, MUC2, MUC5AC, EGFR, and p53 was determined by using immunohistochemistry. Females predominated in those with hepatolithiasis alone and IPNL. The mean age of patients with hepatolithiasis alone was 6 to 8 years younger than that of those with IPNL. The association with hepatolithiasis in patients with IPNL types 1 and 2, IPNL types 3 and 4, and non-IG-ICC was 100%, 79%, and 64%, respectively. Mucobilia, anemia, and elevated serum carcinoembryonic antigen levels were helpful in distinguishing IG-ICC and its precursor lesions. The mean survival of patients with IPNL type 3, IPNL type 4, and non-IG-ICC was 55.5 months, 36.9 months, and 15.8 months, respectively. The incidence of expression of CDX2 and TFF1 was maximal in IPNL type 3. Expression and cellular distribution of MUC2 and CDX2 were similar. MUC5AC was strongly expressed in all patients with IPNL; EGFR and p53 were rarely expressed in patients with IPNL. In conclusion, hepatolithiasis appears to be a precipitating factor in the development of IPNL. Signs of mucobilia were specific for the diagnosis of IPNL. Expression of CDX2 and MUC2 are helpful in differentiating IPNL and non-IG-ICC. Significant differences in survival associated with the various lesions studied warrants a more aggressive surgical strategy in their management. ( I ntrahepatic cholangiocarcinoma (ICC) is a primary adenocarcinoma originating from the second or higher order branches of hepatic bile ducts. The incidence of ICC exhibits wide geographical variations that range from 5% to 30% of primary liver cancers. 1 Various predisposing factors, including liver fluke infestation, hepatolithiasis, primary sclerosing cholangitis, choledochocyst, and Caroli's disease, have been implicated. [1][2][3] In Taiwan, ICC was found in 5% to 10% of patients with hepatolithiasis. 3,4 Based on gross morphology, ICC can be divided into three types (mass-forming, periductalinfiltrating, and intraductal growth [IG]-type). 1 The IG-ICC is the least common type but is associated with the most favorable outcome. 1,5 Biliary papillomatosis, intraductal growth-type cholangiocarcinoma (IG-ICC), and mucin-producing ICC constitute essentially the same disease entity. [5][6][7] This category of papillary biliary neoplasm resembles intraductal papillary mucinous neoplasm of the pancreas histologically. 8 We recently proposed the term intraductal papillary neoplasm of the liver (IPNL) for such lesions, which include both IG-ICC and its precursor lesions. 6,9 Phenotypes of gastrointestinal meta...

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Aberrant expression of CDX2 is closely related to the intestinal metaplasia and MUC2 expression in intraductal papillary neoplasm of the liver in hepatolithiasis

Cited by 75 publications

References 36 publications

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

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

Biliary cystic tumors with bile duct communication: a cystic variant of intraductal papillary neoplasm of the bile duct

Characterization of intrahepatic cholangiocarcinoma of the intraductal growth-type and its precursor lesions

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