TY - JOUR
T1 - Tissue inhibitor of metalloproteinases (TIMP)-1 creates a premetastatic niche in the liver through SDF-1/CXCR4-dependent neutrophil recruitment in mice
AU - Seubert, Bastian
AU - Grünwald, Barbara
AU - Kobuch, Julia
AU - Cui, Haissi
AU - Schelter, Florian
AU - Schaten, Susanne
AU - Siveke, Jens T.
AU - Lim, Ngee H.
AU - Nagase, Hideaki
AU - Simonavicius, Nicole
AU - Heikenwalder, Mathias
AU - Reinheckel, Thomas
AU - Sleeman, Jonathan P.
AU - Janssen, Klaus Peter
AU - Knolle, Percy A.
AU - Krüger, Achim
N1 - Publisher Copyright:
© 2014 by the American Association for the Study of Liver Diseases.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84920950450&partnerID=8YFLogxK
U2 - 10.1002/hep.27378
DO - 10.1002/hep.27378
M3 - Article
C2 - 25131778
AN - SCOPUS:84920950450
SN - 0270-9139
VL - 61
SP - 238
EP - 248
JO - Hepatology
JF - Hepatology
IS - 1
ER -