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

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Abstract

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.

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Abbreviations

DAPI:

4′,6-Diamidine-2-phenylindole

Hgf:

Hepatocyte growth factor

i.v.:

Intraveneous

Met:

Hepatocyte growth factor receptor

MMP:

Matrix metalloproteinase

qRT-PCR:

Quantitative real-time polymerase chain reaction

rec:

Recombinant

SF:

Scatter factor

sh:

Small hairpin

TBS:

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

Timp:

Tissue inhibitor of metalloproteinases

X-Gal:

5-Bromo-4-chloro-3-indolyl-β-d-galactopyranoside

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Acknowledgments

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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Authors and Affiliations

  1. Institut für Experimentelle Onkologie und Therapieforschung des Klinikums rechts der Isar, Technische Universität München, Ismaninger Straße 22, 81675, Munich, Germany

    Florian Schelter, Martina Grandl, Bastian Seubert, Susanne Schaten, Stephanie Hauser, Michael Gerg & Achim Krüger

  2. IRCC-Institute for Cancer Research at Candiolo, Università di Torino, 10060, Candiolo, Italy

    Carla Boccaccio & Paolo Comoglio

Authors
  1. Florian Schelter
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  2. Martina Grandl
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  3. Bastian Seubert
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  4. Susanne Schaten
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  5. Stephanie Hauser
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  6. Michael Gerg
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  7. Carla Boccaccio
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  8. Paolo Comoglio
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  9. Achim Krüger
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Correspondence to Achim Krüger.

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Schelter, F., Grandl, M., Seubert, B. et al. Tumor cell-derived Timp-1 is necessary for maintaining metastasis-promoting Met-signaling via inhibition of Adam-10. Clin Exp Metastasis 28, 793–802 (2011). https://doi.org/10.1007/s10585-011-9410-z

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  • DOI: https://doi.org/10.1007/s10585-011-9410-z

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