The process of cancer invasion and metastasis comprises a complex series of sequential steps. The initial step is the dissociation of cancer cells from the primary tumour through the breakdown of the cell adhesion system which includes integrins, selectins, CD44 and the cadherin families of molecules. Cadherins, which are a family of transmembranous glycoproteins responsible for calcium-dependent intercellular adhesion, bind cells tightly by homophilic interaction in the presence of calcium ions; the inactivation of other adhesion systems has little effect on cellcell adhesion when cadherins are functioning normally'**.
E-cadherin, one of the classical cadherins, plays an important role in epithelial integrity. It has been shown by immunohistochemical techniques to be expressed on the cell-cell boundaries of non-cancerous epithelial cells without exception3. On the other hand, E-cadherin is frequently reduced or absent in cancer cells, which suggests that an impaired E-cadherin-mediated cell-cell adhesion system is a characteristic of cells with malignant transformation.
Previous studies, using immunohistochemical staining and Western blotting, have demonstrated that reduced E-cadherin expression is associated with tumour dedifferentiation, increased invasiveness and a high incidence of lymph node metastasis in a number of human carcinomas. Patients with normal expression of E-cadherin have a better prognosis than those with reduced expression in studies of carcinoma of the head and neck, stomach, bladder, prostate and oesophagus4. These observations are supported by in vitro studies, which have evaluated the influence of E-cadherin function on cell behaviour and suggest a possible role of E-cadherin as an invasion suppressor m~lecule'~~.
Linkage between cadherins and the actin filaments of the cytoskeleton is necessary to form strong cell-cell adhesion. This linkage is localized at the adherens junction and is mediated by many associated junctional undercoat proteins, including catenins, vinculin and actin. Catenins are a group of proteins which interact with the intercellular domain of E-cadherin and comprise a-(102 kDa), p-(88 kDa) and y-(82 kDa)catenin6. The a-catenin gene is located on chromosome 5q21-22 and the p-catenin gene on 3p21.
Many previous reports have suggested that decreased adhesive function of Ecadherin may occur in a number of ways including: (1) downregulation of Ecadherin expression; (2) abnormal catenins, including deletion or mutation in the genes that encode them; and (3) biochemical modification of catenins, for instance the phosphorylation of p-catenin.