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

Charlotte Kopitz, Michael Gerg, Obul Reddy Bandapalli, Dilek Ister, Caroline J. Pennington, Stephanie Hauser, Christin Flechsig, Hans Willi Krell, Dalibor Antolovic, Keith Brew, Hideaki Nagase, Manfred Stangl, Claus W. Hann Von Weyhern, Björn L.D.M. Brücher, Karsten Brand, Lisa M. Coussens, Dylan R. Edwards, Achim Krüger

Research output: Contribution to journalArticlepeer-review

128 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)8615-8623
Number of pages9
JournalCancer Research
Issue number18
StatePublished - Sep 15 2007
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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