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Tissue Inhibitor of Metalloproteinases-1 Promotes Liver Metastasis by Induction of Hepatocyte Growth Factor Signaling

¹ Institut für Experimentelle Onkologie und Therapieforschung, ² Chirurgische Klinik, and ³ Institut für Allgemeine Pathologie und Pathologische Anatomie, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany; ⁴ Institute of Pathology and ⁵ Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany; ⁶ School of Biological Sciences, University of East Anglia, Norwich, Norfolk, United Kingdom; ⁷ Roche Diagnostics GmbH, Penzberg, Germany; ⁸ Department of Biomedical Science, Florida Atlantic University, Boca Raton, Florida; ⁹ The Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, London, United Kingdom; and ¹⁰ Department of Pathology and Comprehensive Cancer Center, University of California, San Francisco, California

Requests for reprints: Achim Krüger, Institut für Experimentelle Onkologie und Therapieforschung, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Str. 22, D-81675 Munich, Germany. Phone: 49-89-4140-4463; Fax: 49-89-4140-6182; E-mail: achim.krueger{at}lrz.tu-muenchen.de.

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. [Cancer Res 2007;67(18):8615–23]

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