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Tissue inhibitor of metalloproteinases-1-induced scattered liver metastasis is mediated by hypoxia-inducible factor-1α

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Abstract

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.

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Abbreviations

Ad:

Adenovirus

BSA:

Bovine serum albumine

CAIX:

Carboanhydrase IX

DAB:

3,3′-Diaminobenzidine

DAPI:

4′,6-Diamidine-2-phenylindole

HEK:

Human embryonic kidney cell

HGF:

Hepatocyte growth factor

HIF:

Hypoxia-inducible factor

HRE:

Hypoxia-responsive element

HRP:

Horseradish peroxidase

i.v.:

Intraveneous

Met:

Hepatocyte growth factor receptor

MMP:

Matrix metalloproteinase

NT:

Non-template

PBS:

Phosphate-buffered saline

Pfu:

Plaque-forming unit

qRT-PCR:

Quantitative real-time polymerase chain reaction

rec:

Recombinant

SDS-PAGE:

Sodiumdodecylsulfate polyacrylamide gel electrophoresis

SEM:

Standard error mean

sh:

Small hairpin

TBS:

2-Amino-2-(hydroxymethyl)-propane-1,3-diole-buffered saline

TIMP:

Tissue inhibitor of metalloproteinases

X-Gal:

5-Bromo-4-chloro-3-indolyl-β-d-galactopyranoside

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Acknowledgments

The author thank Katja Honert, Mareike Lehnhoff, Tina Krause, and Dr Susanne Schaten (all from Institut für Experimentelle Onkologie und Therapieforschung des Klinikums rechts der Isar, Technische Universität München, Munich, Germany) for their expert technical assistance. For financial support, the authors thank the European Union Research Framework Programme 7, project HEALTH-2007-201279/Microenvimet (to Achim Krüger) and project HEALTH-F2-2009-222741/Metoxia (to Agnes Görlach), and the Deutsche Forschungsgemeinschaft, grant KR2047/1-1 (to Achim Krüger).

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Authors and Affiliations

  1. Institut für Experimentelle Onkologie und Therapieforschung des Klinikums rechts der Isar, Technische Universität München, Ismaninger Straße 22, 81675, München, Germany

    Florian Schelter, Birgit Halbgewachs, Petra Bäumler, Caroline Neu, Florian Schrötzlmair & Achim Krüger

  2. Experimentelle Kinderkardiologie des Deutschen Herzzentrums München, Technische Universität München, Lazarettstraße 36, 80636, München, Germany

    Agnes Görlach

Authors
  1. Florian Schelter
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  2. Birgit Halbgewachs
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  3. Petra Bäumler
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  4. Caroline Neu
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  5. Agnes Görlach
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  6. Florian Schrötzlmair
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  7. Achim Krüger
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Correspondence to Achim Krüger.

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Schelter, F., Halbgewachs, B., Bäumler, P. et al. Tissue inhibitor of metalloproteinases-1-induced scattered liver metastasis is mediated by hypoxia-inducible factor-1α. Clin Exp Metastasis 28, 91–99 (2011). https://doi.org/10.1007/s10585-010-9360-x

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  • DOI: https://doi.org/10.1007/s10585-010-9360-x

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