Tissue inhibitor of metalloproteinases-1-induced scattered liver metastasis is mediated by hypoxia-inducible factor-1α.
The "protease web", representing the network of proteases, their inhibitors, and effector molecules, arises as a pivotal determinant of tissue homeostasis. Imbalances of this network, for instance caused by elevated host levels of tissue inhibitor of metalloproteinases-1 (TIMP-1), have been shown to increase the susceptibility of target organs to scattered metastasis by inducing the hepatocyte growth factor (HGF) pathway. Increased expression of the hypoxia-inducible factor-1α-subunit (HIF-1α) is also associated with tumour progression and is also known to induce HGF-signaling via up-regulation of the HGF-receptor Met, namely under canonical stress conditions like lack of oxygen. Here, we aimed to identify a possible metastasis-promoting connection between TIMP-1, HIF-1α, and HGF-signaling. We found that HIF-1α and HIF-1-signaling were increased during liver metastasis of L-CI.5s T-lymphoma cells in TIMP-1 overexpressing syngeneic DBA/2 mice. In vitro, exposure of L-CI.5s cells to recombinant TIMP-1 revealed that TIMP-1 itself was able to induce HIF-1α and HIF-1-signaling. Knock-down of HIF-1α identified tumour cell-derived HIF-1α as mediator of this TIMP-1-induced invasiveness in vitro. In vivo, HIF-1α knock-down significantly impaired Met expression as well as Met phosphorylation and inhibited scattered liver metastasis. Furthermore, HGF-dependent TIMP-1-promoted Met phosphorylation and HGF-dependent TIMP-1-induced invasiveness in vitro was mediated by HIF-1α. We conclude that elevated levels of TIMP-1 in the microenvironment of tumour cells can promote metastasis by inducing HIF-1α-dependent HGF-signaling. This connection between a protease inhibitor (TIMP-1) and a classically stress-related factor (HIF-1α) is a so far undiscovered impact of the "protease web" on tissue homeostasis with important implications for metastasis.
Institut für Experimentelle Onkologie und Therapieforschung des Klinikums rechts der Isar, Technische Universität München, Ismaninger Strasse 22, 81675, München, Germany.
Florian
F
Schelter
Birgit
B
Halbgewachs
Petra
P
Bäumler
Caroline
C
Neu
Agnes
A
Görlach
Florian
F
Schrötzlmair
Achim
A
Krüger
D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008811:Mice, Inbred DBA; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D015854:Up-Regulation
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019715:Tissue Inhibitor of Metalloproteinase-1; D019859:Proto-Oncogene Proteins c-met