Regulation of monocyte MMP-9 production by TNF-alpha and a tumour-derived soluble factor (MMPSF).
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.
Leber
T M
TM
Imperial Cancer Research Fund London, UK.
Balkwill
F R
FR
D002450:Cell Communication; D018920:Coculture Techniques; D017364:Collagenases / Q000235:genetics / Q000378:metabolism*; D017077:Culture Media, Conditioned; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D020780:Matrix Metalloproteinase 9; D009000:Monocytes / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
D017077:Culture Media, Conditioned; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D017364:Collagenases; D020780:Matrix Metalloproteinase 9