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. 1998 Sep;78(6):724–732. doi: 10.1038/bjc.1998.568

Regulation of monocyte MMP-9 production by TNF-alpha and a tumour-derived soluble factor (MMPSF).

T M Leber 1, F R Balkwill 1
PMCID: PMC2062959  PMID: 9743290

Abstract

The matrix metalloprotease MMP-9 localizes to tumour-associated macrophages in human ovarian cancer but little is known of its regulation. Co-culture of human ovarian cancer cells (PEO-1) and a monocytic cell line (THP-1) led to production of 92-kDa proMMP-9. PEO-1-conditioned medium (CM) also stimulated THP-1 cells or isolated peripheral blood monocytes to produce proMMP-9. Expression of TIMP-1, however, remained unaffected. There was evidence that tumour necrosis factor alpha (TNF-alpha) was involved in tumour-stimulated monocytic proMMP-9 production. Antibody to TNF-alpha inhibited proMMP-9 production, and synthesis of TNF-alpha mRNA and protein preceded proMMP-9 release. In addition, the synthetic matrix metalloprotease inhibitor (MMPI) BB-2116, which blocks TNF-alpha shedding, inhibited proMMP-9 release in the co-cultures and from CM-stimulated monocytic cells. Further experiments suggested that the stimulating factor present in CM was not TNF-alpha, but acted synergistically with autocrine monocyte-derived TNF-alpha to release monocytic proMMP-9. Thus, ovarian cancer cells can stimulate monocytic cells in vitro to make proMMP-9 without affecting the expression of its inhibitor TIMP-1. This induction is mediated via a soluble factor (provisionally named MMPSF) that requires synergistic action of autocrine or paracrine TNF-alpha.

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Selected References

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