Plasminogen activator inhibitor-2, but not cystatin C, inhibits the prometastatic activity of tissue inhibitor of metalloproteinases-1 in the liver.
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.
Kopitz
Charlotte
C
Klinikum Rechts der Isar der Technischen Universität München, Institut für Experimentelle Onkologie und Therapieforschung, D-81675 Munich, Germany.
Gerg
Michael
M
Gansbacher
Bernd
B
Krüger
Achim
A
D000818:Animals; D045744:Cell Line, Tumor; D055316:Cystatin C / Q000096:biosynthesis*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D005354:Fibrosarcoma / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D017396:Plasminogen Activator Inhibitor 2 / Q000096:biosynthesis*; D010960:Plasminogen Activators / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis*
C525031:Cst3 protein, mouse; D055316:Cystatin C; D017396:Plasminogen Activator Inhibitor 2; D019715:Tissue Inhibitor of Metalloproteinase-1; D010960:Plasminogen Activators; D003546:Cysteine Endopeptidases