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

Br J Cancer. 1998 Sep;78(6):724-32. doi: 10.1038/bjc.1998.568.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Communication
  • Coculture Techniques
  • Collagenases / genetics
  • Collagenases / metabolism*
  • Culture Media, Conditioned
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression Regulation
  • Humans
  • Matrix Metalloproteinase 9
  • Monocytes / metabolism
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Ovarian Neoplasms / metabolism
  • RNA, Messenger / metabolism
  • Tissue Inhibitor of Metalloproteinase-1 / genetics
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism*
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology


  • Culture Media, Conditioned
  • Neoplasm Proteins
  • RNA, Messenger
  • Tissue Inhibitor of Metalloproteinase-1
  • Tumor Necrosis Factor-alpha
  • Collagenases
  • Matrix Metalloproteinase 9