Tissue inhibitor of metalloproteinases (TIMP)-1 creates a premetastatic niche in the liver through SDF-1/CXCR4-dependent neutrophil recruitment in mice
Due to its ability to inhibit prometastatic matrix metalloproteinases, tissue inhibitor of metalloproteinases (TIMP)-1 has been thought to suppress tumor metastasis. However, elevated systemic levels of TIMP-1 correlate with poor prognosis in cancer patients, suggesting a metastasis-stimulating role...
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| Hauptverfasser: | , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
24 November 2014
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| In: |
Hepatology
Year: 2014, Jahrgang: 61, Heft: 1, Pages: 238-248 |
| ISSN: | 1527-3350 |
| DOI: | 10.1002/hep.27378 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1002/hep.27378 Verlag, kostenfrei, Volltext: http://onlinelibrary.wiley.com.ezproxy.medma.uni-heidelberg.de/doi/10.1002/hep.27378/abstract 
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| Verfasserangaben: | Bastian Seubert, Barbara Grünwald, Julia Kobuch, Haissi Cui, Florian Schelter, Susanne Schaten, Jens T. Siveke, Ngee H. Lim, Hideaki Nagase, Nicole Simonavicius, Mathias Heikenwalder, Thomas Reinheckel, Jonathan P. Sleeman, Klaus-Peter Janssen, Percy A. Knolle, and Achim Krüger |
| Zusammenfassung: | Due to its ability to inhibit prometastatic matrix metalloproteinases, tissue inhibitor of metalloproteinases (TIMP)-1 has been thought to suppress tumor metastasis. However, elevated systemic levels of TIMP-1 correlate with poor prognosis in cancer patients, suggesting a metastasis-stimulating role of TIMP-1. In colorectal cancer patients, tumor as well as plasma TIMP-1 levels were correlated with synchronous liver metastasis or distant metastasis-associated disease relapse. In mice, high systemic TIMP-1 levels increased the liver susceptibility towards metastasis by triggering the formation of a premetastatic niche. This promoted hepatic metastasis independent of origin or intrinsic metastatic potential of tumor cells. High systemic TIMP-1 led to increased hepatic SDF-1 levels, which in turn promoted recruitment of neutrophils to the liver. Both inhibition of SDF-1-mediated neutrophil recruitment and systemic depletion of neutrophils reduced TIMP-1-induced increased liver susceptibility towards metastasis. This indicates a crucial functional role of neutrophils in the TIMP-1-induced premetastatic niche. Conclusion: Our results identify TIMP-1 as an essential promoter of hepatic premetastatic niche formation. |
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| Beschreibung: | Gesehen am 16.08.2017 |
| Beschreibung: | Online Resource |
| ISSN: | 1527-3350 |
| DOI: | 10.1002/hep.27378 |