Potentiation of metastasis by cell surface sialomucin complex (rat MUC4), a multifunctional anti-adhesive glycoprotein

Abstract

Sialomucin complex (SMC), a rat homologue of the human mucin MUC4, is a large membrane-bound mucin complex, originally isolated from highly metastatic ascites 13762 mammary adenocarcinoma cells. When overexpressed, SMC exerts potent anti-adhesive effects, which sterically disrupt molecular interactions for cell-cell and cell-ECM adhesions. SMC similarly suppresses anti-tumor immunity by inhibition of interactions between cytotoxic lymphocytes and target tumor cells. Previously, recombinant cDNAs for SMC were transfected and inducibly expressed in A375 human melanoma cells using a tetracycline-responsive expression system. In the current studies, we investigated the role of MUC4/SMC in tumor metastasis by regulating SMC expression of tumor transplants in vivo. Intravenous injection of SMC-overexpressing cells resulted in substantially greater lung metastasis than injection of SMC-repressed cells. Injection of SMC-overexpressing cells followed by in vivo downregulation of SMC did not lower the frequency of lung metastasis. Growth of the micrometastatic lesions was the same for all 3 cases in short-term (3-week) assays. Further, subcutaneous injection of A375 cells followed by in vivo induction of SMC overexpression within the solid tumor resulted in spontaneous distant metastasis. These studies suggest that SMC potentiates metastasis by contributing to the establishment of metastatic foci. These studies directly demonstrate for the first time that tumor metastasis can be modulated by the regulation of MUC4/SMC expression.