Clinical & Experimental Metastasis

, Volume 28, Issue 8, pp 793–802

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 Krüger
Research Paper

DOI: 10.1007/s10585-011-9410-z

Cite this article as:
Schelter, F., Grandl, M., Seubert, B. et al. Clin Exp Metastasis (2011) 28: 793. doi:10.1007/s10585-011-9410-z

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.

Keywords

Hgf Liver metastasis Met Protease web Timp-1 

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

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
  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