Membrane-type I matrix metalloproteinase-dependent ectodomain shedding of mucin16/CA-125 on ovarian cancer cells modulates adhesion and invasion of peritoneal mesothelium.

Mucin16 [MUC16/cancer antigen 125 (CA-125)],a high-molecular-weight glycoprotein expressed on the ovarian tumor cell surface,potentiates metastasis via selective binding to mesothelin on peritoneal mesothelial cells. Shed MUC16/CA-125 is detectable in sera from ovarian cancer patients. We investigated the potential role of membrane type 1 matrix metalloproteinase (MT1-MMP,MMP-14),a transmembrane collagenase highly expressed in ovarian cancer cells,in MUC16/CA-125 ectodomain shedding. An inverse correlation between MT1-MMP and MUC16 immunoreactivity was observed in human ovarian tumors and cells. Further,when MUC16-expressing OVCA433 cells were engineered to overexpress MT1-MMP,surface expression of MUC16/CA-125 was lost,whereas cells expressing the inactive E240A mutant retained surface MUC16/CA-125. As a functional consequence,decreased adhesion of cells expressing catalytically active MT1-MMP to three-dimensional meso-mimetic cultures and intact ex vivo peritoneal tissue explants was observed. Nevertheless,meso-mimetic invasion is enhanced in MT1-MMP-expressing cells. Together,these data support a model wherein acquisition of catalytically active MT1-MMP expression in ovarian cancer cells induces MUC16/CA-125 ectodomain shedding,reducing adhesion to meso-mimetic cultures and to intact peritoneal explants. However,proteolytic clearing of MUC16/CA-125,catalyzed by MT1-MMP,may then expose integrins for high-affinity cell binding to peritoneal tissues,thereby anchoring metastatic lesions for subsequent proliferation within the collagen-rich sub-mesothelial matrix.