title: Tissue inhibitor of metalloproteinases (TIMP)-1 creates a premetastatic niche in the liver through SDF-1/CXCR4-dependent neutrophil recruitment in mice.
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.
  
  
  CONCLUSIONS
  Our results identify TIMP-1 as an essential promoter of hepatic premetastatic niche formation.
authors.affiliation: Institut für Experimentelle Onkologie und Therapieforschung, Institute of Molecular Immunology Technische Universität München, München, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Seubert
authors.forename: Barbara
authors.initials: B
authors.lastname: Grünwald
authors.forename: Julia
authors.initials: J
authors.lastname: Kobuch
authors.forename: Haissi
authors.initials: H
authors.lastname: Cui
authors.forename: Florian
authors.initials: F
authors.lastname: Schelter
authors.forename: Susanne
authors.initials: S
authors.lastname: Schaten
authors.forename: Jens T
authors.initials: JT
authors.lastname: Siveke
authors.forename: Ngee H
authors.initials: NH
authors.lastname: Lim
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nagase
authors.forename: Nicole
authors.initials: N
authors.lastname: Simonavicius
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.forename: Thomas
authors.initials: T
authors.lastname: Reinheckel
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Sleeman
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Janssen
authors.forename: Percy A
authors.initials: PA
authors.lastname: Knolle
authors.forename: Achim
authors.initials: A
authors.lastname: Krüger
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000097:blood / Q000556:secondary*; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008113:Liver Neoplasms / Q000097:blood / Q000556:secondary*; D051379:Mice; D008815:Mice, Inbred Strains; D041681:NIH 3T3 Cells; D020556:Neutrophil Infiltration; D019718:Receptors, CXCR4 / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood / Q000378:metabolism*
chemical_list: D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; C560822:TIMP1 protein, human; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1