TY - JOUR
T1 - Tissue inhibitor of metalloproteinases-1 promotes liver metastasis by induction of hepatocyte growth factor signaling
AU - Kopitz, Charlotte
AU - Gerg, Michael
AU - Bandapalli, Obul Reddy
AU - Ister, Dilek
AU - Pennington, Caroline J.
AU - Hauser, Stephanie
AU - Flechsig, Christin
AU - Krell, Hans Willi
AU - Antolovic, Dalibor
AU - Brew, Keith
AU - Nagase, Hideaki
AU - Stangl, Manfred
AU - Hann Von Weyhern, Claus W.
AU - Brücher, Björn L.D.M.
AU - Brand, Karsten
AU - Coussens, Lisa M.
AU - Edwards, Dylan R.
AU - Krüger, Achim
PY - 2007/9/15
Y1 - 2007/9/15
N2 - Balanced expression of proteases and their inhibitors is one prerequisite of tissue homeostasis. Metastatic spread of tumor cells through the organism depends on proteolytic activity and is the death determinant for cancer patients. Paradoxically, increased expression of tissue inhibitor of metalloproteinases-1 (TIMP-1), a natural inhibitor of several endometalloproteinases, including matrix metalloproteinases and a disintegrin and metalloproteinase-10 (ADAM-10), in cancer patients is negatively correlated with their survival, although TIMP-1 itself inhibits invasion of some tumor cells. Here, we show that elevated stromal expression of TIMP-1 promotes liver metastasis in two independent tumor models by inducing the hepatocyte growth factor (HGF) signaling pathway and expression of several metastasis-associated genes, including HGF and HGF-activating proteases, in the liver. We also found in an in vitro assay that suppression of ADAM-10 is in principle able to prevent shedding of cMet, which may be one explanation for the increase of cell-associated HGF receptor cMet in livers with elevated TIMP-1. Similar TIMP-1-associated changes in gene expression were detected in livers of patients with metastatic colorectal cancer. The newly identified role of TIMP-1 to create a prometastatic niche may also explain the TIMP-1 paradoxon.
AB - Balanced expression of proteases and their inhibitors is one prerequisite of tissue homeostasis. Metastatic spread of tumor cells through the organism depends on proteolytic activity and is the death determinant for cancer patients. Paradoxically, increased expression of tissue inhibitor of metalloproteinases-1 (TIMP-1), a natural inhibitor of several endometalloproteinases, including matrix metalloproteinases and a disintegrin and metalloproteinase-10 (ADAM-10), in cancer patients is negatively correlated with their survival, although TIMP-1 itself inhibits invasion of some tumor cells. Here, we show that elevated stromal expression of TIMP-1 promotes liver metastasis in two independent tumor models by inducing the hepatocyte growth factor (HGF) signaling pathway and expression of several metastasis-associated genes, including HGF and HGF-activating proteases, in the liver. We also found in an in vitro assay that suppression of ADAM-10 is in principle able to prevent shedding of cMet, which may be one explanation for the increase of cell-associated HGF receptor cMet in livers with elevated TIMP-1. Similar TIMP-1-associated changes in gene expression were detected in livers of patients with metastatic colorectal cancer. The newly identified role of TIMP-1 to create a prometastatic niche may also explain the TIMP-1 paradoxon.
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UR - http://www.scopus.com/inward/citedby.url?scp=34548749917&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-07-0232
DO - 10.1158/0008-5472.CAN-07-0232
M3 - Article
C2 - 17875701
AN - SCOPUS:34548749917
SN - 0008-5472
VL - 67
SP - 8615
EP - 8623
JO - Cancer Research
JF - Cancer Research
IS - 18
ER -