METASTASIS-ASSOCIATED 5T4 ANTIGEN DISRUPTS CELL-CELL CONTACTS AND INDUCES CELLULAR MOTILITY IN EPITHELIAL-CELLS

The 5T4 antigen is defined by a monoclonal antibody (MAb) specific for human trophoblast. It is also expressed by many types of tumour cell and has been associated with metastasis and poor clinical outcome in a number of cancers. This pattern of expression is consistent with a me chanistic involvement of 5T4 molecules in the spread of cancer cells. The 5T4 antigen is a transmembrane glycoprotein with a 310 amino acid extracellular domain and a 44 amino acid cytoplasmic domain. Transfect ion of full-length 5T4 cDNA into epithelial cells alters cell-cell con tacts and cellular motility. Thus, in 5T4-transfected CL-SI murine mam mary cells, 5T4 expression is associated with dendritic morphology, ac companied by abrogation of actin/cadherin-containing contacts and incr eased motility. In transfected MDCK canine kidney epithelial cells, 5T 4 over-expression also results in increased motility, but disruption o f cell-cell contacts, either by culturing cells in low calcium medium or by addition of HGF/SF, is needed. The effects of 5T4 expression an morphology and motility are separable since cells transfected with a t runcated form of 5T4 cDNA in which the cytoplasmic domain is deleted r eveal that the latter is necessary to abrogate actin/cadherin containi ng contacts but does not influence the effects on motility. Thus, 5T4 molecules can deliver signals through both the extracellular and intra cellular domains, and the resultant effects are consistent with a role for 5T4 molecules in invasion processes. (C) 1996 Wiley-Liss, Inc.