E-Cadherin Deficiency Initiates Gastric Signet-Ring Cell Carcinoma in Mice and Man
| Autor: | Bostjan Humar, Iain G. Martin, Helen More, Parry Guilford, Amanda Charlton, Vanessa Blair |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Cancer Research
Pathology medicine.medical_specialty Tumor initiation Biology CDH1 Mice Antigens CD Stomach Neoplasms Signet ring cell carcinoma medicine Animals Humans Promoter Regions Genetic Cell Proliferation Cadherin Cancer DNA Methylation Cadherins medicine.disease Mice Inbred C57BL Oncology Tumor progression DNA methylation biology.protein Cancer research Hereditary diffuse gastric cancer Carcinoma Signet Ring Cell |
| Zdroj: | Cancer Research. 69:2050-2056 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | The importance of loss of the cell-cell adhesion molecule E-cadherin (encoded by CDH1) to tumor progression is well established. However, CDH1 germ-line mutations predispose to the cancer susceptibility syndrome hereditary diffuse gastric cancer (HDGC), suggesting a role for E-cadherin in tumor initiation. The earliest indications of cancer in the stomachs of CDH1 mutation carriers are microscopic foci of intramucosal signet-ring cell carcinoma (SRCC; designated “eHDGC”). Here, we used N-methyl-N-nitrosourea (MNU) to promote gastric carcinogenesis in wild-type (wt) and cdh1+/− mice. MNU induced a variety of gastric tumors; however, intramucosal SRCC developed with an 11 times higher incidence in cdh1+/− mice compared with wt mice. The murine SRCC resembled the human eHDGCs in that they were hypoproliferative, lacked nuclear β-catenin accumulation, and had reduced membrane localization of E-cadherin and its interacting junctional proteins. The down-regulation of E-cadherin in the murine SRCCs confirmed the importance of the second CDH1 hit to the initiation of diffuse gastric cancer. CDH1 promoter hypermethylation has been proposed to be a major second hit in advanced HDGC; however, its contribution to eHDGC was unknown. We thus examined a series of human eHDGC and detected CDH1 promoter methylation in 50% of foci. Promoter methylation was accompanied by reduced wt CDH1 mRNA levels in the foci and had a monoclonal pattern, consistent with an epigenetic initiation of disease. Together, these findings provide compelling evidence for a deficiency in cell-to-cell adhesion being sufficient to initiate diffuse gastric cancer in the absence of hyperproliferation and β-catenin activation. [Cancer Res 2009;69(5):2050–6] |
| Databáze: | OpenAIRE |
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