Fibronectin and other extracellular molecules play crucial roles in cell adhesion, migration, and invasion. Polypeptide recognition sequences necessary for cell interactions with fibronectin and other proteins are being characterized by synthetic peptide analyses and site-directed mutagenesis. A variety of synthetic peptide inhibitors from fibronectin, laminin, and collagen were compared as inhibitors of the migration of several types of human tumor cells. Peptides containing the Arg-Gly-Asp sequence were the most effective. Anti-integrin antibodies were particularly effective inhibitors. Anti-alpha5 and anti-alpha2 monoclonal antibodies displayed specificity depending on the ligand used for the migration substrate, i.e. for fibronectin and collagen, respectively. An anti-beta1 monoclonal antibody was the most general inhibitor on various substrates, as well as inhibiting tumor cell invasion at microgram concentrations. Collaborative studies are being completed on a cell-type specific adhesion site used by melanomas and some lymphocytes. The minimal critical sequence appears to be Leu-Asp-Val; this sequence is also present in other adhesion proteins. A novel heat-shock protein previously shown to be decreased after malignant transformation was found to bind specifically to fetuin as well as to collagen, indicating a broader function than previously known. Studies will continue on other crucial polypeptide sequences, on their roles in adhesion, migration, and invasion, and on developing novel inhibitors of their functions.
