Analysis of &lt;i&gt;β-Catenin&lt;/i&gt; Gene Mutations in Pancreatic Tumors

Gerdes, Berthold; Ramaswamy, Annette; Simon, Babette; Pietsch, Torsten; Daniel, Bastian; Kersting, Michael; Moll, Roland; Bartsch, Detlef K.

doi:10.1159/000007704

Cited by 69 publications

(44 citation statements)

References 13 publications

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“…Aberrant expression of E-cadherin and its related catenins has been reported in a number of human cancers and their precursor lesions (28 -33). Our result that revealed the loss of E-cadherin expression in 36% of pancreatic ductal cancers was consistent with previous reports, which reported rates that ranged from 42% to 60% (15)(16)(17)(18)(19)(20). The marked increase in cytoplasmic E-cadherin immunoreactivity in PanIN lesions compared with normal pancreatic ducts signifies relocation of E-cadherin from the plasma membrane to the cytoplasm.…”

Section: Ink4asupporting

confidence: 93%

“…Expression of E-cadherin and ␤-catenin has been studied in pancreatic adenocarcinomas (15)(16)(17)(18)(19)(20). Consistently with Ecadherin and, less so, with ␤-catenin, their reduced/absent expression or aberrant localization has been associated with a poorer differentiation, infiltrative growth pattern, higher stage, lymph node metastasis, and, in some studies, with cancer specific survival.…”

Section: Introductionmentioning

confidence: 99%

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Epithelial-Cadherin and β-Catenin Expression Changes in Pancreatic Intraepithelial Neoplasia

Al-Aynati

Radulovich

Riddell

et al. 2004

Clinical Cancer Research

100

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Purpose: Cadherins and associated catenins are important mediators of epithelial cell-cell adhesion, as well as the Wnt-signaling pathway. Significant changes in their expression or structure have been implicated in malignancy. This study aimed to investigate the epithelial-cadherin (Ecadherin) and ␤-catenin expression changes during multistage, pancreatic ductal carcinogenesis.Experimental Design: Ninety-four Whipple resection specimens were retrieved from the surgical pathology files of the University Health Network (Toronto, Canada), from which tissue microarray blocks containing 36 pancreatic ductal adenocarcinomas, 34 PanIN-1A lesions, 28 PanIN-1B lesions, 27 PanIN-2 lesions, 16 PanIN-3 lesions, and 32 normal ducts were constructed. The E-cadherin, ␤-catenin, and the phosphorylated glycogen synthase kinase-3␤ of the Wnt/ ␤-catenin pathway were immunohistochemically evaluated in these duct/PanIN lesions.Results: There was marked increase in the cytoplasmic E-cadherin expression in PanIN lesions (P < 0.0001) and adenocarcinoma (P ‫؍‬ 0.005) compared with normal pancreatic ducts. In contrast, reduced/loss of E-cadherin membranous expression was also significant in ductal adenocarcinoma compared with both the PanIN lesions (P < 0.0001) and normal ducts (P ‫؍‬ 0.05). The ␤-catenin expression showed significantly more frequent aberrant nuclear localization in high-grade PanIN lesions, particularly PanIN2 and in adenocarcinoma compared with normal ducts or low grade PanIN lesions (P < 0.0001). However, there was a lack of correlation between phospho Ser9 -glycogen synthase kinase-3␤ cytoplasmic expression and ␤-catenin aberrant nuclear expression (P ‫؍‬ 0.07).Conclusions: Aberration in the expression of Ecadherin and its associated ␤-catenin is evident in preinvasive (PanIN) neoplastic pancreatic duct cells, suggesting involvement of pathways leading to ␤-catenin stabilization during pancreatic duct cell carcinogenesis.

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Section: Ink4asupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Epithelial-Cadherin and β-Catenin Expression Changes in Pancreatic Intraepithelial Neoplasia

Al-Aynati

Radulovich

Riddell

et al. 2004

Clinical Cancer Research

100

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“…These findings support a correlation between beta-catenin abnormalities and fascin expression; however, it should be noted that pancreatic adenocarcinomas overexpress fascin but do not harbor beta-catenin mutations. 17,56 Therefore other mechanisms must be also involved in up-regulating fascin overexpression. 57 hsp47 hsp47, heat shock protein 47 or colligin, is a collagen-specific chaperone that is essential for development and collagen molecular maturation in the ER.…”

Section: Fascinmentioning

confidence: 99%

Expression of novel markers of pancreatic ductal adenocarcinoma in pancreatic nonductal neoplasms: additional evidence of different genetic pathways

et al. 2005

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Solid pseudopapillary tumor, pancreatoblastoma, undifferentiated carcinoma with osteoclastic-like giant cells, and acinar cell carcinomas are rare pancreatic nonductal neoplasms. Compared to the significant advances in our understanding of the pathogenesis of pancreatic ductal adenocarcinomas in the last decades, the molecular mechanisms underlying pancreatic nonductal neoplasms are poorly understood. In order to elucidate their molecular pathogenesis, we constructed tissue microarrays to study the expression of some novel pancreatic ductal adenocarcinoma-associated tumor markers in these nonductal pancreatic neoplasms. We analyzed nine markers including tumor suppressor gene (14-3-3 sigma), proliferation marker (topoisomerase II alpha), epithelial markers (prostate stem cell antigen, mesothelin and cytokeratin 19), stromal markers (fascin, hsp47 and fibronectin), and gamma-synuclein whose function is not delineated. In addition, we included tumor suppressor gene DPC4 and oncogene Beta-catenin to further confirm their expression in pancreatic nonductal tumors. Our results showed that in contrast to pancreatic ductal adenocarcinomas that show loss of Dpc4 protein in 55% of cases, loss of Dpc4 expression is absent in pancreatic nonductal neoplasms. Expression of 14-3-3 sigma is frequently seen in both pancreatic nonductal neoplasms (25-100%) and ductal adenocarcinomas (89%). Aberrant nuclear expression of beta-catenin is common in pancreatic nonductal neoplasms, specifically in solid pseudopapillary tumors (88%) and pancreatoblastomas (100%) but is rarely seen in pancreatic ductal adenocarcinomas (o5%). Expression of topoisomerase II alpha is not seen in solid pseudopapillary tumors and undifferentiated carcinomas with osteoclastic-like giant cells but is focally seen in pancreatoblastomas (50%) and acinar cell carcinomas (85%). Expression of PSCA and mesothelin was observed in pancreatic nonductal neoplasms but their expression was seen less frequently (0-50%) and weaker than that in pancreatic ductal adenocarcinomas (60-100%). CK19, a marker of pancreatic ductal adenocarcinomas, is not expressed in pancreatic nonductal neoplasms. Expression of gamma-synuclein as well as stromal markers (fascin, hsp47 and fibronectin) is frequently seen in both. Our findings indicate pancreatic nonductal neoplasms have distinctive patterns of protein expression relative to pancreatic ductal adenocarcinomas and suggest that pancreatic nonductal neoplasms have different genetic pathways from the more common pancreatic ductal adenocarcinomas.

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“…LS174T cells harbored mutant APC protein, HCT116, and AGS, have mutant b-catenin protein, and Colo357 and Panc-1 cells have intact Wnt signaling. [28][29][30][31][32] …”

Section: Up-regulation Of the B-catenin/tcf Signaling Pathway In Gastmentioning

confidence: 99%

Suppression of gastric cancer cell growth by targeting the β‐catenin/T‐cell factor pathway

Dvory‐Sobol

Sagiv

Liberman

et al. 2007

Cancer

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BACKGROUND.Functional activation of β‐catenin/T‐cell factor (Tcf) signaling plays an important role in the early events of carcinogenesis. Recently, it was demonstrated that adenomatous polyposis coli or β‐catenin genes are mutated frequently in gastric cancer cells. The objective of the current study was to use a gene‐targeting approach to kill human gastric cancer cells selectively with activated β‐catenin/Tcf signaling.METHODS.A recombinant adenovirus that carries a lethal gene (p53 up‐regulated modulator of apoptosis [PUMA]) under the control of a β‐catenin/Tcf‐responsive promoter (AdTOP‐PUMA) was used selectively to target gastric cancer cells (AGS) that posses an active β‐catenin/Tcf pathway. The combined effect of AdTOP‐PUMA and several chemotherapeutic agents (5‐florouracil, doxorubicin, paclitaxel) also was evaluated. Cell viability was measured by methylene blue assay, protein expression was measured by Western blot analysis, and cell cycle and apoptosis were evaluated by fluorescent‐activated cell sorter analysis.RESULTS.The TOP‐PUMA adenovirus inhibited AGS cell growth in a dose‐ and time‐dependent fashion. Growth inhibition was associated with the up‐regulation of PUMA expression and the induction of apoptosis. Chemotherapy synergistically enhanced the killing effect of AdTOP‐PUMA.CONCLUSIONS.Selective targeting of gastric cancer cells with the activated β‐catenin pathway may be a novel and effective therapy in gastric cancer. Combination of this gene‐therapy approach with standard therapy may improve efficacy and reduce toxicity. Cancer 2007. © 2006 American Cancer Society.

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Analysis of <i>β-Catenin</i> Gene Mutations in Pancreatic Tumors

Cited by 69 publications

References 13 publications

Epithelial-Cadherin and β-Catenin Expression Changes in Pancreatic Intraepithelial Neoplasia

Epithelial-Cadherin and β-Catenin Expression Changes in Pancreatic Intraepithelial Neoplasia

Expression of novel markers of pancreatic ductal adenocarcinoma in pancreatic nonductal neoplasms: additional evidence of different genetic pathways

Suppression of gastric cancer cell growth by targeting the β‐catenin/T‐cell factor pathway

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