Tissue inhibitor of metalloproteinases (TIMP)-1 creates a premetastatic niche in the liver through SDF-1/CXCR4-dependent neutrophil recruitment in mice

• Verfasst von: Seubert, Bastian [VerfasserIn]
• Verfasst von: Sleeman, Jonathan P. [VerfasserIn]
• Titel: Tissue inhibitor of metalloproteinases (TIMP)-1 creates a premetastatic niche in the liver through SDF-1/CXCR4-dependent neutrophil recruitment in mice
• Verf.angabe: 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
• E-Jahr: 2015
• Jahr: 24 November 2014
• Jahr des Originals: 2014
• Umfang: 11 S.
• Fussnoten: Gesehen am 16.08.2017
• Titel Quelle: Enthalten in: Hepatology
• Ort Quelle: [Alphen aan den Rijn] : Wolters Kluwer Health, 1981
• Jahr Quelle: 2015
• Band/Heft Quelle: 61(2015), 1, Seite 238-248
• ISSN Quelle: 1527-3350
• DOI: doi:10.1002/hep.27378
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1562468111

Abstract

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.