MT1-MMP AND MMP-2 MESSENGER-RNA EXPRESSION IN HUMAN OVARIAN-TUMORS - POSSIBLE IMPLICATIONS FOR THE ROLE OF DESMOPLASTIC FIBROBLASTS

Expression of activated MMP-2 (72 kDa type IV collagenase) is highly a ssociated with the malignant phenotype in adenocarcinomas, but predomi nant expression of the mRNA appears to be in stromal cells. MT1-MMP (m embrane type 1-matrix metalloproteinase) is implicated in tumor-epithe lial cell surface activation of latent pro-MMP-2, indicating a mechani sm for rumor-stromal interaction in invasion. We determined the relati ve mRNA distribution of these MMPs in human ovarian tumors with a view to analyzing potential variations in the epithelial-mesenchymal inter actions dictating ovarian tumor cell spread. In situ hybridization usi ng S-35-labeled riboprobes was used to analyze 33 human ovarian tumors and mouse xenografts of human ovarian (DOV 13, SKOV3) and breast (MCF 7) tumor cell lines known to express MT1-MMP and MMP-2. MMP-2 mRNA was expressed in 31 of 33 and MT1-MMP mRNA was expressed in 29 of 33 tumo r cases, MMP-2 mRNA was predominantly expressed in desmoplastic fibrob lasts and in the subepithelial stroma. MT1-MMP mRNA showed some coloca lization with MMP-2 in stromal cells. Neoplastic epithelial cell label ing for MT1-MMP mRNA was present in borderline and malignant tumors bu t not in benign tumors, and was invariably less than stromal labeling. Xenografts of DOV 13, SKOV 3, and MCF 7 cells showed some stromal loc alization of MMP-2 mRNA and weak labeling of DOV 13 cells. There was v ariable labeling for MT1-MMP mRNA in the neoplastic cells only. The co localization of MT1-MMP and MMP-2 mRNAs in ovarian carcinoma stroma su pports the view that MT1-MMP is closely associated with MMP-2 expressi on and function. It suggests that either additional mechanisms are inv olved in regulating MMP-2 activation at the tumor cell surface, or mor e intriguingly, that desmoplastic fibroblasts may be the primary media tors of extracellular matrix remodeling with respect to this system. C opyright (C) 1998 by W.B. Saunders Company.