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Effects of Thomsen-Friedenreich Antigen-specific Peptide P-30 on ß-Galactoside-mediated Homotypic Aggregation and Adhesion to the Endothelium of MDA-MB-435 Human Breast Carcinoma Cells¹

Cancer Research Center [V. V. G.] and Department of Biochemistry [V. V. G., S. L. D., T. P. Q.], University of Missouri, Columbia, Missouri 65211; La Jolla Institute for Allergy and Immunology [M. E. H.], San Diego, California 92121; and Sidney Kimmel Cancer Center and Metastat, Inc. [G. V. G.], San Diego, California 92121

Both the ability of malignant cells to form multicellular aggregates via homotypic or heterotypic aggregation and their adhesion to the endothelium are important if not critical during early stages of cancer metastasis. The tumor-associated carbohydrate Thomsen-Friedenreich antigen (T antigen) and ß-galactoside binding lectins (galectins) have been implicated in tumor cell adhesion and tissue invasion. In this study, we demonstrate the involvement of T antigen in both homotypic aggregation of MDA-MB-435 human breast carcinoma cells and their adhesion to the endothelium. The T antigen-specific peptide P-30 (HGRFILPWWYAFSPS) selected from a bacteriophage display library was able to inhibit spontaneous homotypic aggregation of MDA-MB-435 cells up to 74% in a dose-dependent manner. Because T antigen has ß-galactose as a terminal sugar, the expression profile of ß-galactoside-binding lectins (galectins) in MDA-MB-435 cells was studied. Our data indicated the abundant expression of [³⁵S]methionine/cysteine-labeled galectin-1 and galectin-3 in this cell line, which suggested possible interactions between galectins and T antigen. As revealed by laser confocal microscopy, both galectin-1 and galectin-3 also participate in the adhesion of the MDA-MB-435 cells to the endothelium. We observed the clustering of galectin-3 on endothelial cells at the sites of the contact with tumor cells, consistent with its possible interaction with T antigen on cancer cells. The galectin-1 signal, however, strongly accumulated at the sites of cell-cell contacts predominantly on tumor cells. The T antigen-specific P-30 significantly (50%) inhibited this adhesion, which indicated that T antigen participates in the adhesion of MDA-MB-435 breast cancer cells to the endothelium. The ability of synthetic P-30 to inhibit both the spontaneous homotypic aggregation of MDA-MB-435 cells and their adhesion to the endothelium (>70 and 50%, respectively) suggests its potential functional significance for antiadhesive therapy of cancer metastasis.

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