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Tumor cell-derived Timp-1 is necessary for maintaining metastasis-promoting Met-signaling via inhibition of Adam-10.
- Source :
-
Clinical & experimental metastasis [Clin Exp Metastasis] 2011 Dec; Vol. 28 (8), pp. 793-802. Date of Electronic Publication: 2011 Jul 26. - Publication Year :
- 2011
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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.
- Subjects :
- ADAM Proteins genetics
ADAM10 Protein
Amyloid Precursor Protein Secretases genetics
Animals
Blotting, Western
Cell Proliferation
Cells, Cultured
Gene Expression Regulation, Neoplastic
Hepatocyte Growth Factor pharmacology
Humans
Kidney cytology
Kidney metabolism
Liver Neoplasms, Experimental genetics
Liver Neoplasms, Experimental metabolism
Membrane Proteins genetics
Mice
Mice, Inbred DBA
Phosphorylation drug effects
Proto-Oncogene Proteins c-met antagonists & inhibitors
Proto-Oncogene Proteins c-met genetics
RNA, Messenger genetics
RNA, Small Interfering genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Survival Rate
Tissue Inhibitor of Metalloproteinase-1 antagonists & inhibitors
Tissue Inhibitor of Metalloproteinase-1 genetics
ADAM Proteins antagonists & inhibitors
ADAM Proteins metabolism
Amyloid Precursor Protein Secretases antagonists & inhibitors
Amyloid Precursor Protein Secretases metabolism
Liver Neoplasms, Experimental secondary
Membrane Proteins antagonists & inhibitors
Membrane Proteins metabolism
Proto-Oncogene Proteins c-met metabolism
Tissue Inhibitor of Metalloproteinase-1 metabolism
Tumor Microenvironment
Subjects
Details
- Language :
- English
- ISSN :
- 1573-7276
- Volume :
- 28
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Clinical & experimental metastasis
- Publication Type :
- Academic Journal
- Accession number :
- 21789719
- Full Text :
- https://doi.org/10.1007/s10585-011-9410-z