Plasminogen activator inhibitor-2, but not cystatin C, inhibits the prometastatic activity of tissue inhibitor of metalloproteinases-1 in the liver

Hum Gene Ther. 2008 Oct;19(10):1039-49. doi: 10.1089/hum.2008.078.


Formation of multiple and scattered metastases in target organs, leading to disruption of organ functional integrity, is the death-determining step for most lethal cancers. In the clinic, elevated expression of tissue inhibitor of metalloproteinases-1 (TIMP-1) is often associated with increased aggressiveness of cancer. We demonstrated that elevated host expression of TIMP-1 leads to the promotion of scattered liver metastases in mice, associated with increased activity of cysteine proteases (CPs). This study aimed for reduction of TIMP-1-promoted experimental liver metastases of lacZ-tagged human fibrosarcoma cells by overexpression of cystatin C, a natural inhibitor of CPs, in the murine host. Although CP inhibition reduced TIMP-induced proteolytic activity, the TIMP-1-induced increase in total tumor cell burden in livers was not significantly reduced. However, overexpression of cystatin C in livers with elevated TIMP-1 led to the formation of large multicellular metastatic foci in 42% of the mice. This formation was associated with increased expression of plasminogen activators (PAs). Additional overexpression of plasminogen activator inhibitor-2 prevented the formation of macrometastatic foci as well as the TIMP-1-induced increase in total tumor cell burden. This demonstrates that PAs are crucial for the prometastatic activity of TIMP-1 and led to the assumption that patients with elevated TIMP-1 expression may benefit from an antiproteolytic treatment directed against PAs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cystatin C / biosynthesis*
  • Cysteine Endopeptidases / metabolism
  • Fibrosarcoma / metabolism*
  • Fibrosarcoma / pathology
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Liver Neoplasms / secondary
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis
  • Plasminogen Activator Inhibitor 2 / biosynthesis*
  • Plasminogen Activators / metabolism
  • Tissue Inhibitor of Metalloproteinase-1 / biosynthesis*


  • Cst3 protein, mouse
  • Cystatin C
  • Plasminogen Activator Inhibitor 2
  • Tissue Inhibitor of Metalloproteinase-1
  • Plasminogen Activators
  • Cysteine Endopeptidases