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

Sialomucin complex (SMC), a rat homologue of the human mucin MUC4, is a lar ge 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 interacti ons for cell-cell and cell-ECM adhesions. SMC similarly suppresses anti-tum or 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 r ole of MUC4/SMC in tumor metastasis by regulating SMC expression of tumor t ransplants in vivo. Intravenous injection of SMC-overexpressing cells resul ted in substantially greater lung metastasis than injection of SMC-represse d cells. Injection of SMC-overexpressing cells followed by in vivo downregu lation 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 spontan eous distant metastasis. These studies suggest that SMC potentiates metasta sis by contributing to the establishment of metastatic foci, These studies directly demonstrate for the first time that tumor metastasis can be modula ted by the regulation of MUC4/SMC expression. Int. J. Cancer 87:480-486, 20 00. (C) 2000 Wiley-Liss, Inc.