Dynamic alteration of the E-cadherin/catenin complex during cell differentiation and invasion of undifferentiated-type gastric carcinomas.

To examine qualitative alterations of the E-cadherin/catenin complex (CCC) during cell differentiation and invasion of undifferentiated-type gastric carcinoma, immunoreactivity for the intracytoplasmic domain and the extracellular domain (ECD) of E-cadherin, and that of beta-catenin, was analysed in the mucosal, submucosal, and deepest invasive parts of 20 early and 20 advanced cancers that had a component of intramucosal signet ring cell carcinoma. Histological subtype affected the mode of E-CCC alteration. The tumours with a tubular component and without organized differentiation of signet ring cells in a layered structure were associated with nuclear expression of beta-catenin and may derive from tubular adenocarcinomas through de-differentiation and de-regulation of the Wnt pathway. These tumours were characterized by relatively stable ECD expression throughout the course of tumour progression. On the other hand, the tumours with a layered structure, which may derive from signet ring cell carcinoma by de novo abnormality of E-cadherin, were characterized by dynamic alteration of ECD expression during cell differentiation and tumour progression; intramucosal spread (with a layered structure) as well as deep invasion (beyond the submucosa) commonly showed cellular dissociation with downregulation of ECD, whereas submucosal invasion and lymph node metastasis often showed cellular cohesion and retention (or 'reappearance') of ECD. Thus, cellular dissociation did not always reflect enhanced invasive activity but may be reversibly regulated during tumour progression.