Tissue inhibitor of metalloproteinases-1 promotes liver metastasis by induction of hepatocyte growth factor signaling

Cancer Res. 2007 Sep 15;67(18):8615-23. doi: 10.1158/0008-5472.CAN-07-0232.


Balanced expression of proteases and their inhibitors is one prerequisite of tissue homeostasis. Metastatic spread of tumor cells through the organism depends on proteolytic activity and is the death determinant for cancer patients. Paradoxically, increased expression of tissue inhibitor of metalloproteinases-1 (TIMP-1), a natural inhibitor of several endometalloproteinases, including matrix metalloproteinases and a disintegrin and metalloproteinase-10 (ADAM-10), in cancer patients is negatively correlated with their survival, although TIMP-1 itself inhibits invasion of some tumor cells. Here, we show that elevated stromal expression of TIMP-1 promotes liver metastasis in two independent tumor models by inducing the hepatocyte growth factor (HGF) signaling pathway and expression of several metastasis-associated genes, including HGF and HGF-activating proteases, in the liver. We also found in an in vitro assay that suppression of ADAM-10 is in principle able to prevent shedding of cMet, which may be one explanation for the increase of cell-associated HGF receptor cMet in livers with elevated TIMP-1. Similar TIMP-1-associated changes in gene expression were detected in livers of patients with metastatic colorectal cancer. The newly identified role of TIMP-1 to create a prometastatic niche may also explain the TIMP-1 paradoxon.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / antagonists & inhibitors
  • ADAM Proteins / metabolism
  • ADAM10 Protein
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Cell Growth Processes / physiology
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Hepatocyte Growth Factor / metabolism*
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Liver Neoplasms / secondary*
  • Male
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Nude
  • Middle Aged
  • NIH 3T3 Cells
  • Proto-Oncogene Proteins c-met / metabolism
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Signal Transduction
  • Tissue Inhibitor of Metalloproteinase-1 / biosynthesis*
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism


  • Membrane Proteins
  • RNA, Messenger
  • Tissue Inhibitor of Metalloproteinase-1
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met
  • Amyloid Precursor Protein Secretases
  • ADAM Proteins
  • ADAM10 Protein
  • ADAM10 protein, human