E-Cadherin Deficiency Initiates Gastric Signet-Ring Cell Carcinoma in Mice and Man

Bostjan Humar,Vanessa Blair,Helen More,Iain Martin,Amanda Charlton,Parry Guilford

doi:10.1158/0008-5472.can-08-2457

Bostjan Humar, Vanessa Blair + Show 4 more

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https://doi.org/10.1158/0008-5472.can-08-2457

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Abstract

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 beta-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 beta-catenin activation.

Highlights

Perceptions of the initiating events in cancer usually involve a hyperproliferative state caused by mutations in genes implicated in cell cycle control or cell survival
Mice not treated with MNU showed few cancers: 1 of 20 cdh1+/À mice had a signet-ring cell carcinoma (SRCC), whereas no tumors were seen in the wt mice
MNU-treated cdh1+/À mice developed murine SRCCs with an 11 times higher incidence than the MNU-treated wt mice (P < 0.002; Table 1). These results show that SRCCs in the cdh1+/À mice developed in addition to the background adenomas induced by MNU in both cdh1+/À and wt mice

Summary

Introduction

Perceptions of the initiating events in cancer usually involve a hyperproliferative state caused by mutations in genes implicated in cell cycle control or cell survival. The identification of the gene for the cell-cell adhesion molecule E-cadherin (CDH1) as a cancer susceptibility gene [1], has raised the possibility that an event as superficially simple as lost adhesion may be sufficient to initiate cancer. E-cadherin, the key component of the epithelial adherens junction, is required for the proper formation and maintenance of epithelial sheets [2]. Additional proteins that participate in the adherens junctions include h-catenin, a structural component and an essential transducer of Wnt pathway signals, p120 catenin, required for the complex stability, and Lin-7, which is found only in mature adherens junctions [3, 4]

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