Loss of E-cadherin in mouse gastric epithelial cells induces signet ring-like cells, a possible precursor lesion of diffuse gastric cancer.

Alterations in the E-cadherin gene are associated with sporadic and hereditary diffuse-type gastric cancer. To determine how the loss of function of E-cadherin affects gastric epithelial cell phenotypes, we generated transgenic mice using the Cre-loxP system in which the E-cadherin gene is specifically knocked out in the parietal cell lineage. In the transgenic mice, expression of E-cadherin was lost or reduced in proton pump-expressing parietal cells, which became round in shape and were pushed out of the glands to accumulate in the stromal area. Additionally, gastric mucosa exhibited hyperplasia from 3 months in the mice, some cells of which later became positive for trefoil factor 2, a marker of spasmolytic polypeptide-expressing metaplasia. From 6 months, E-cadherin-negative/proton pump-negative cells appeared from the parietal cell lineage, which increased in number to form cell clusters. Moreover, signet ring-like cells, which are morphologically similar to signet ring carcinoma cells, were found in the cell clusters from 12 months. However, no invasive gastric adenocarcinomas were found in the E-cadherin-deficient mice, even at 24 months or later. These data indicate that the loss of E-cadherin induces possible pre-cancerous lesions in the gastric mucosa but may not be sufficient for its malignant conversion.