A cDNA encoding the cell-cell adhesion molecule E-cadherin was transfected tnto highly invasive epithelial tumor cell lines of dog kidney or mouse mammary gland origin. Transfectants with a homogeneously high expression of E-cadherin showed a reproducible loss of activity in two types of in vitro invasion assays. invasiveness of these transfectants could be reinduced specifically by treatment with anti-bcadherin antibodies. In vivo, they formed partly differentiated tumors, instead of fully undifferentiated tumors. Alternatively, a plasmid encoding E-cadherin-specific antisense RNA was introduced into noninvasive rastransformed ceils with high endogenous E-cadherin expression. The resulting down-regulation, albeit partial, rendered the cells invasive. These data provide direct evidence that E-cadherin acts as an invasion suppressor molecule. introduction

Epithelial cell tumors, ie, carcinomas, constitute 900/6 of human malignancies. Invasion and metastasis of these tumors are major causes of therapeutic failure (Fidler and Balch, 1987). Invasion is a hallmark of malignancy and a prerequisite for metastasis (Liotta, 1986; Nicolson, 1988; Mareel et al., 1990, 1991b). In a collaborative effort, we previously found suggestive evidence for an anti-invasive role of E-cadherin: epithelial Madin-Darby canine kidney (MDCK) cells acquired invasive capacity in vitro when treated with monoclonal anti-E-cadherin antibodies, whereas ras-transformed MDCK cells were invasive without prior antibody treatment only if they lacked E-cadherin expression (Behrens et al., 1989). E-cadherin is a cell-cell adhesion molecule (CAM) synonymous with or homologous to the transmembrane glycoproteins uvomorulin, L-CAM, cell-CAM 120/80, or Arc-l (reviewed by Edelman, 1988; Takeichi, 1988, 199O). It plays a key role in the Ca*+-dependent homophilic adhesion between epithelial cells and is implicated in normal morphogenesis. Its disregulated expression might be related to invasion and metastasis. Decreased adhesion of tumor cells to neighboring tumor or host cells would favor their emigration from the local site and their penetration of extracellular matrices. This is in agreement with the “three-step theory of invasion” advanced by Liotta (1986) where locomotion, together with adhesion to the basement membrane and