MMP-2 release and activation in ovarian carcinoma: the role of fibroblasts

The matrix metalloproteinase MMP-2 is up-regulated in epithelial cancers and its mRNA localizes to stromal fibroblasts. In this paper we show that co-culture of ovarian carcinoma cells with fibroblasts resulted in an enhanced release of proMMP-2 and TIMP-2 into the culture medium. Cell-cell interaction was a major factor in this response and carcinoma cells stimulated proMMP-2 release from fibroblasts but not vice versa. Collagen 1, in a dose-dependent fashion, induced activation of proMMP-2 by tumour-derived, but not normal, fibroblasts. Antibody to beta1 integrin also induced proMMP-2 activation by tumour-derived fibroblasts. The activation involved the processing of proMMP-2 by a membrane-bound metalloproteinase. We propose that, in the ovarian tumour microenvironment, interaction between tumour cells and fibroblasts may enhance fibroblast production of the proMMP-2 and TIMP-2. Collagen I, also present in the ovarian tumours, then induces these fibroblasts to activate proMMP-2 even in the presence of TIMP-2. This active MMP-2 can associate with the cell surface of tumour cells and fibroblasts and is used in the processes of tissue remodelling and invasion.