Clinical & Experimental Metastasis

, Volume 28, Issue 8, pp 793–802 | Cite as

Tumor cell-derived Timp-1 is necessary for maintaining metastasis-promoting Met-signaling via inhibition of Adam-10

  • Florian Schelter
  • Martina Grandl
  • Bastian Seubert
  • Susanne Schaten
  • Stephanie Hauser
  • Michael Gerg
  • Carla Boccaccio
  • Paolo Comoglio
  • Achim KrügerEmail author
Research Paper


In many different tumor entities, increased expression of tissue inhibitor of metalloproteinases-1 (Timp-1) is associated with poor prognosis. We previously reported in mouse models that elevated systemic levels of Timp-1 induce a gene expression signature in the liver microenvironment increasing the susceptibility of this organ to tumor cells. This host effect was dependent on increased activity of the hepatocyte growth factor (Hgf)/hepatocyte growth factor receptor (Met) signaling pathway. In a recent study we showed that Met signaling is regulated by Timp-1 as it inhibits the Met sheddase A disintegrin and metalloproteinase-10 (Adam-10). The aim of the present study was to elucidate whether the metastatic potential of tumor cells benefits from autocrine Timp-1 as well and involves Adam-10 and Met signaling. In a syngeneic murine model of experimental liver metastasis Timp-1 expression and Met signaling were localized within metastatic colonies and expressed by tumor cells. Knock down of tumor cell Timp-1 suppressed Met signaling in metastases and inhibited metastasis formation and tumor cell-scattering in the liver. In vitro, knock down of tumor cell Timp-1 prevented Hgf-induced Met phosphorylation. Consequently, knock down of Met sheddase Adam-10 triggered auto-phosphorylation and responsiveness to Hgf. Accordingly, Adam-10 knock down increased Met phosphorylation in metastatic foci and induced tumor cell scattering into the surrounding liver parenchyma. In conclusion, these findings show that tumor cell-derived Timp-1 acts as a positive regulator of the metastatic potential and support the concept that proteases and their natural inhibitors, as members of the protease web, are major players of signaling during normal homeostasis and disease.


Hgf Liver metastasis Met Protease web Timp-1 





Hepatocyte growth factor




Hepatocyte growth factor receptor


Matrix metalloproteinase


Quantitative real-time polymerase chain reaction




Scatter factor


Small hairpin


2-Amino-2-(hydroxymethyl)-propane-1,3-diole-buffered saline


Tissue inhibitor of metalloproteinases





We thank Katja Honert and Stefan Grötzinger (all from Institut für Experimentelle Onkologie und Therapieforschung des Klinikums rechts der Isar, Technische Universität München, Munich, Germany) for their expert technical assistance and Gillian Murphy for providing the anti-Timp-1 antibody. For financial support, the authors thank the European Union Research Framework Programme 7, project HEALTH-2007-201279/Microenvimet (to Achim Krüger, Carla Boccaccio and Paolo Comoglio).


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Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Florian Schelter
    • 1
  • Martina Grandl
    • 1
  • Bastian Seubert
    • 1
  • Susanne Schaten
    • 1
  • Stephanie Hauser
    • 1
  • Michael Gerg
    • 1
  • Carla Boccaccio
    • 2
  • Paolo Comoglio
    • 2
  • Achim Krüger
    • 1
    Email author
  1. 1.Institut für Experimentelle Onkologie und Therapieforschung des Klinikums rechts der IsarTechnische Universität MünchenMunichGermany
  2. 2.IRCC-Institute for Cancer Research at CandioloUniversità di TorinoCandioloItaly

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