Overexpression of sialomucin complex, a rat homologue of MUC4, inhibits tumor killing by lymphokine-activated killer cells

Sialomucin complex (SMC) is a large heterodimeric glycoprotein complex comp osed of a mucin subunit ascites sialoglycoprotein-l and a transmembrane sub unit ascites sialoglycoprotein-2, It is a rat homologue of human mucin gene MUC4 and is abundantly expressed on the cell surface of highly metastatic ascites 13762 rat mammary adenocarcinoma cells, Because of their extended a nd rigid structures, mucin-type glycoproteins are suggested to have suppres sing effects on cell-cell and cell-matrix interactions. During the metastat ic process, these effects presumably cause tumor cell detachment from the p rimary tumor mass and facilitate escape of the tumor cells from immunosurve illance. Analyses of human breast cancer cells in solid tumors and tumor ef fusions showed that the more aggressive cells in effusions are stained with polyclonal antibodies against SMC more frequently than cells in solid tumo rs, suggesting a role for MUC4/SMC in tumor progression and metastasis, Pre viously, we generated recombinant cDNAs for SMC that vary in the number of mucin repeats to study the putative functions of SMC in tumor metastasis, T hese cDNAs were transfected into human cancer cell lines and tested for the effect of the expression of this gene. Here, using a tetracycline-responsi ve inducible expression system, we demonstrate that overexpression of SMC m asks the surface antigens on target tumor cells and effectively suppresses tumor cell killing by cytotoxic lymphocytes, This effect results from the a bility of SMC to block killer cell binding to the tumor cells and is depend ent on both overexpression of the mucin and the number of mucin repeats in the expressed SMC, These results provide an explanation for the proposed ro le of SMC/MUC4 in tumor progression.