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.
Imperial Cancer Research Fund, London, UK.
R S
RS
Boyd
F R
FR
Balkwill
D000818:Animals; D002450:Cell Communication; D002462:Cell Membrane / Q000201:enzymology; D018920:Coculture Techniques; D003094:Collagen / Q000494:pharmacology; D003470:Culture Media; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D018093:Gelatinases / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000502:physiology; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured
D003470:Culture Media; D004792:Enzyme Precursors; D016023:Integrins; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D018093:Gelatinases; D008666:Metalloendopeptidases; C069860:progelatinase; D020778:Matrix Metalloproteinase 2