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

<div>Abstract<p>The importance of loss of the cell-cell adhesion molecule E-cadherin (encoded by <i>CDH1</i>) to tumor progression is well established. However, <i>CDH1</i> 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 <i>CDH1</i> mutation carriers are microscopic foci of intramucosal signet-ring cell carcinoma (SRCC; designated “eHDGC”). Here, we used <i>N</i>-methyl-<i>N</i>-nitrosourea (MNU) to promote gastric carcinogenesis in wild-type (wt) and <i>cdh1^+/−</i> mice. MNU induced a variety of gastric tumors; however, intramucosal SRCC developed with an 11 times higher incidence in <i>cdh1^+/−</i> 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 <i>CDH1</i> hit to the initiation of diffuse gastric cancer. <i>CDH1</i> 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 <i>CDH1</i> promoter methylation in 50% of foci. Promoter methylation was accompanied by reduced wt <i>CDH1</i> 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]</p></div>