Tissue inhibitor of metalloproteinases-1-induced scattered liver metastasis is mediated by host-derived urokinase-type plasminogen activator.
Paradoxically, not only proteinases but also their inhibitors can correlate with bad prognosis of cancer patients, underlining the evolving concept of the protease web as the complex interplay between proteinases, their inhibitors and effector molecules. Elevated levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) render the liver more susceptible to metastasis by triggering urokinase plasminogen activator (uPA) expression as well as hepatocyte growth factor (HGF) signalling, thereby leading to the fatal scattered infiltration of metastasizing tumour cells throughout the parenchyma of the target organ. Here, we investigated whether host uPA is a crucial protagonist for the TIMP-1-induced modulation of a pro-metastatic microenvironment in the liver. Indeed, in livers of uPA-ablated mice elevated TIMP-1 levels did not trigger HGF signalling and did not promote metastasis of a murine T-lymphoma cell line. In contrast, lack of tumour cell-derived uPA induced by gene silencing did not interfere with this pro-metastatic pathway. Furthermore, host uPA was necessary for the recruitment of neutrophilic granulocytes and the associated increase of HGF in livers with elevated TIMP-1 levels. This newly identified co-operation between TIMP-1 and host uPA suggests that therapies, simultaneously interfering with pro- and anti-proteolytic pathways may be beneficial for patients with metastatic disease.
Institut für Experimentelle Onkologie und Therapieforschung, Klinikum rechts der Isar der Technischen Universität, Munich, Germany.
Florian
F
Schrötzlmair
Charlotte
C
Kopitz
Birgit
B
Halbgewachs
Fei
F
Lu
Hana
H
Algül
Nils
N
Brünner
Bernd
B
Gänsbacher
Achim
A
Krüger
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006098:Granulocytes / Q000276:immunology; D057809:HEK293 Cells; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000276:immunology; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D018345:Mice, Knockout; D011379:Prognosis; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D019715:Tissue Inhibitor of Metalloproteinase-1; D017228:Hepatocyte Growth Factor; D014568:Urokinase-Type Plasminogen Activator