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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 publication

DOI

10.1158/0008-5472.can-07-0232

Type

Journal article

Journal

Cancer research

Publication Date

09/2007

Volume

67

Pages

8615 - 8623

Addresses

Institut für Experimentelle Onkologie und Therapieforschung, Universität München, Munich, Germany.

Keywords

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