Expression and activity of MMPS and their regulators in ovarian cancer.

In order to understand the ability of human ovarian cancers to degrade the basement membrane, we have studied the localization and activity of matrix metalloproteases (MMPs) 2 and 9, using in situ hybridization and quantificative zymography on sequential sections of tumor biopsies. We have related these data to expression of some of the controlling elements of the enzymes, namely tissue inhibitors of metastasis (TIMPs) and tumor necrosis factor (TNF). mRNA for MMP-2 was found in the majority of cases and localized to stromal areas with maximal expression adjacent to neoplastic areas. MMP-9 expression was associated with cells in epithelial and stromal areas, consistent with distribution of macrophages. Zymography revealed higher levels of MMP-9 activity in the ovarian cancer biopsy samples than in other cancers studied, but in contrast to our previous observations in breast and bladder cancer, there was no correlation between MMP levels and tumor grade. Nor was there any association between amount of TNF mRNA and levels of MMP enzymes. TIMP-I expression was localized to stromal areas adjacent to tumor epithelial cells as well as, in some cases, to epithelial cells. The pattern of TIMP-2 expression was similar to that of MMP-2. We conclude that the stromal elements of ovarian tumors express MMP-2 and 9 and their specific inhibitors, but these do not seem to be controlled by endogenous TNF in the tumor microenvironment.