Advertisement

Clinical & Experimental Metastasis

, Volume 28, Issue 8, pp 793–802 | Cite as

Tumor cell-derived Timp-1 is necessary for maintaining metastasis-promoting Met-signaling via inhibition of Adam-10

  • Florian Schelter
  • Martina Grandl
  • Bastian Seubert
  • Susanne Schaten
  • Stephanie Hauser
  • Michael Gerg
  • Carla Boccaccio
  • Paolo Comoglio
  • Achim KrügerEmail author
Research Paper

Abstract

In many different tumor entities, increased expression of tissue inhibitor of metalloproteinases-1 (Timp-1) is associated with poor prognosis. We previously reported in mouse models that elevated systemic levels of Timp-1 induce a gene expression signature in the liver microenvironment increasing the susceptibility of this organ to tumor cells. This host effect was dependent on increased activity of the hepatocyte growth factor (Hgf)/hepatocyte growth factor receptor (Met) signaling pathway. In a recent study we showed that Met signaling is regulated by Timp-1 as it inhibits the Met sheddase A disintegrin and metalloproteinase-10 (Adam-10). The aim of the present study was to elucidate whether the metastatic potential of tumor cells benefits from autocrine Timp-1 as well and involves Adam-10 and Met signaling. In a syngeneic murine model of experimental liver metastasis Timp-1 expression and Met signaling were localized within metastatic colonies and expressed by tumor cells. Knock down of tumor cell Timp-1 suppressed Met signaling in metastases and inhibited metastasis formation and tumor cell-scattering in the liver. In vitro, knock down of tumor cell Timp-1 prevented Hgf-induced Met phosphorylation. Consequently, knock down of Met sheddase Adam-10 triggered auto-phosphorylation and responsiveness to Hgf. Accordingly, Adam-10 knock down increased Met phosphorylation in metastatic foci and induced tumor cell scattering into the surrounding liver parenchyma. In conclusion, these findings show that tumor cell-derived Timp-1 acts as a positive regulator of the metastatic potential and support the concept that proteases and their natural inhibitors, as members of the protease web, are major players of signaling during normal homeostasis and disease.

Keywords

Hgf Liver metastasis Met Protease web Timp-1 

Abbreviations

DAPI

4′,6-Diamidine-2-phenylindole

Hgf

Hepatocyte growth factor

i.v.

Intraveneous

Met

Hepatocyte growth factor receptor

MMP

Matrix metalloproteinase

qRT-PCR

Quantitative real-time polymerase chain reaction

rec

Recombinant

SF

Scatter factor

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

Notes

Acknowledgments

We thank Katja Honert and Stefan Grötzinger (all from Institut für Experimentelle Onkologie und Therapieforschung des Klinikums rechts der Isar, Technische Universität München, Munich, Germany) for their expert technical assistance and Gillian Murphy for providing the anti-Timp-1 antibody. For financial support, the authors thank the European Union Research Framework Programme 7, project HEALTH-2007-201279/Microenvimet (to Achim Krüger, Carla Boccaccio and Paolo Comoglio).

References

  1. 1.
    Terpos E, Dimopoulos MA, Shrivastava V et al (2010) High levels of serum TIMP-1 correlate with advanced disease and predict for poor survival in patients with multiple myeloma treated with novel agents. Leuk Res 34(3):399–402PubMedCrossRefGoogle Scholar
  2. 2.
    Aaberg-Jessen C, Christensen K, Offenberg H et al (2009) Low expression of tissue inhibitor of metalloproteinases-1 (TIMP-1) in glioblastoma predicts longer patient survival. J Neurooncol 95(1):117–128PubMedCrossRefGoogle Scholar
  3. 3.
    Scrideli CA, Cortez MA, Yunes JA et al (2010) mRNA expression of matrix metalloproteinases (MMPs) 2 and 9 and tissue inhibitor of matrix metalloproteinases (TIMPs) 1 and 2 in childhood acute lymphoblastic leukemia: potential role of TIMP1 as an adverse prognostic factor. Leuk Res 34(1):32–37PubMedCrossRefGoogle Scholar
  4. 4.
    Rauvala M, Puistola U, Turpeenniemi-Hujanen T (2005) Gelatinases and their tissue inhibitors in ovarian tumors; TIMP-1 is a predictive as well as a prognostic factor. Gynecol Oncol 99(3):656–663PubMedCrossRefGoogle Scholar
  5. 5.
    Chirco R, Liu XW, Jung KK et al (2006) Novel functions of TIMPs in cell signaling. Cancer Metastasis Rev 25(1):99–113PubMedCrossRefGoogle Scholar
  6. 6.
    Mook OR, Frederiks WM, Van Noorden CJ (2004) The role of gelatinases in colorectal cancer progression and metastasis. Biochim Biophys Acta 1705(2):69–89PubMedGoogle Scholar
  7. 7.
    Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2(3):161–174PubMedCrossRefGoogle Scholar
  8. 8.
    Coussens LM, Fingleton B, Matrisian LM (2002) Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295(5564):2387–2392PubMedCrossRefGoogle Scholar
  9. 9.
    Deryugina EI, Quigley JP (2006) Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev 25(1):9–34PubMedCrossRefGoogle Scholar
  10. 10.
    Gutierrez-Fernandez A, Fueyo A, Folgueras AR et al (2008) Matrix metalloproteinase-8 functions as a metastasis suppressor through modulation of tumor cell adhesion and invasion. Cancer Res 68(8):2755–2763PubMedCrossRefGoogle Scholar
  11. 11.
    Garg P, Sarma D, Jeppsson S et al (2010) Matrix metalloproteinase-9 functions as a tumor suppressor in colitis-associated cancer. Cancer Res 70(2):792–801PubMedCrossRefGoogle Scholar
  12. 12.
    Krüger A et al (2001) Hydroxamate-type matrix metalloproteinase inhibitor batimastat promotes liver metastasis. Cancer Res 61(4):1272–1275PubMedGoogle Scholar
  13. 13.
    Schelter F, Halbgewachs B, Baumler P et al (2011) Tissue inhibitor of metalloproteinases-1-induced scattered liver metastasis is mediated by hypoxia-inducible factor-1alpha. Clin Exp Metastasis 28(2):91–99PubMedCrossRefGoogle Scholar
  14. 14.
    Kopitz C, Gerg M, Bandapalli OR et al (2007) Tissue inhibitor of metalloproteinases-1 promotes liver metastasis by induction of hepatocyte growth factor signaling. Cancer Res 67(18):8615–8623PubMedCrossRefGoogle Scholar
  15. 15.
    Krüger A (2009) Functional genetic mouse models: promising tools for investigation of the proteolytic internet. Biol Chem 390(2):91–97PubMedCrossRefGoogle Scholar
  16. 16.
    Overall CM, Kleifeld O (2006) Tumour microenvironment—opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer 6(3):227–239PubMedCrossRefGoogle Scholar
  17. 17.
    Krüger A, Kates RE, Edwards DR (2010) Avoiding spam in the proteolytic internet: future strategies for anti-metastatic MMP inhibition. Biochim Biophys Acta 1803(1):95–102PubMedCrossRefGoogle Scholar
  18. 18.
    Gerg M, Kopitz C, Schaten S et al (2008) Distinct functionality of tumor cell-derived gelatinases during formation of liver metastases. Mol Cancer Res 6(3):341–351PubMedCrossRefGoogle Scholar
  19. 19.
    Schelter F, Gerg M, Halbgewachs B et al (2010) Identification of a survival-independent metastasis-enhancing role of hypoxia-inducible factor-1alpha with a hypoxia-tolerant tumor cell line. J Biol Chem 285(34):26182–26189PubMedCrossRefGoogle Scholar
  20. 20.
    Naldini L, Weidner KM, Vigna E et al (1991) Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor. EMBO J 10(10):2867–2878PubMedGoogle Scholar
  21. 21.
    Boccaccio C, Comoglio PM (2006) Invasive growth: a MET-driven genetic programme for cancer and stem cells. Nat Rev Cancer 6(8):637–645PubMedCrossRefGoogle Scholar
  22. 22.
    Trusolino L, Bertotti A, Comoglio PM (2010) MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol 11(12):834–848PubMedCrossRefGoogle Scholar
  23. 23.
    Comoglio PM, Giordano S, Trusolino L (2008) Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov 7(6):504–516PubMedCrossRefGoogle Scholar
  24. 24.
    Murphy G (2008) The ADAMs: signalling scissors in the tumour microenvironment. Nat Rev Cancer 8(12):929–941PubMedCrossRefGoogle Scholar
  25. 25.
    Amour A, Knight CG, Webster A et al (2000) The in vitro activity of ADAM-10 is inhibited by TIMP-1 and TIMP-3. FEBS Lett 473(3):275–279PubMedCrossRefGoogle Scholar
  26. 26.
    Schelter F, Kobuch J, Moss ML et al (2010) A disintegrin and metalloproteinase-10 (ADAM-10) mediates DN30 antibody-induced shedding of the met surface receptor. J Biol Chem 285(34):26335–26340PubMedCrossRefGoogle Scholar
  27. 27.
    Schirrmeister W, Gnad T, Wex T et al (2009) Ectodomain shedding of E-cadherin and c-Met is induced by Helicobacter pylori infection. Exp Cell Res 315(20):3500–3508PubMedCrossRefGoogle Scholar
  28. 28.
    Koshariya M, Jagad RB, Kawamoto J et al (2007) An update and our experience with metastatic liver disease. Hepatogastroenterology 54(80):2232–2239PubMedGoogle Scholar
  29. 29.
    Sporn MB (1996) The war on cancer. Lancet 347(9012):1377–1381PubMedCrossRefGoogle Scholar
  30. 30.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674PubMedCrossRefGoogle Scholar
  31. 31.
    Krüger A, Schirrmacher V, von Hoegen P (1994) Scattered micrometastases visualized at the single-cell level: detection and re-isolation of lacZ-labeled metastasized lymphoma cells. Int J Cancer 58(2):275–284PubMedCrossRefGoogle Scholar
  32. 32.
    Soneoka Y, Cannon PM, Ramsdale EE et al (1995) A transient three-plasmid expression system for the production of high titer retroviral vectors. Nucleic Acids Res 23(4):628–633PubMedCrossRefGoogle Scholar
  33. 33.
    Krüger A, Schirrmacher V, Khokha R (1998) The bacterial lacZ gene: an important tool for metastasis research and evaluation of new cancer therapies. Cancer Metastasis Rev 17(3):285–294PubMedCrossRefGoogle Scholar
  34. 34.
    Schrötzlmair F, Kopitz C, Halbgewachs B et al (2010) Tissue inhibitor of metalloproteinases-1-induced scattered liver metastasis is mediated by host-derived urokinase-type plasminogen activator. J Cell Mol Med 14(12):2760–2770PubMedCrossRefGoogle Scholar
  35. 35.
    Brand K et al (2000) Treatment of colorectal liver metastases by adenoviral transfer of tissue inhibitor of metalloproteinases-2 into the liver tissue. Cancer Res 60(20):5723–5730PubMedGoogle Scholar
  36. 36.
    Baker AH, Edwards DR, Murphy G (2002) Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci 115(Pt 19):3719–3727PubMedCrossRefGoogle Scholar
  37. 37.
    Bajou K et al (1998) Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med 4(8):923–928PubMedCrossRefGoogle Scholar
  38. 38.
    Krüger A, Fata JE, Khokha R (1997) Altered tumor growth and metastasis of a T-cell lymphoma in Timp-1 transgenic mice. Blood 90(5):1993–2000PubMedGoogle Scholar
  39. 39.
    Elezkurtaj S, Kopitz C, Baker AH et al (2004) Adenovirus-mediated overexpression of tissue inhibitor of metalloproteinases-1 in the liver: efficient protection against T-cell lymphoma and colon carcinoma metastasis. J Gene Med 6(11):1228–1237PubMedCrossRefGoogle Scholar
  40. 40.
    Brew K, Nagase H (2010) The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta 1803(1):55–71PubMedCrossRefGoogle Scholar
  41. 41.
    Foveau B et al (2009) Down-regulation of the met receptor tyrosine kinase by presenilin-dependent regulated intramembrane proteolysis. Mol Biol Cell 20(9):2495–2507PubMedCrossRefGoogle Scholar
  42. 42.
    Amour A et al (1998) TNF-alpha converting enzyme (TACE) is inhibited by TIMP-3. FEBS Lett 435(1):39–44PubMedCrossRefGoogle Scholar
  43. 43.
    Moss ML, Stoeck A, Yan W et al (2008) ADAM10 as a target for anti-cancer therapy. Curr Pharm Biotechnol 9(1):2–8PubMedCrossRefGoogle Scholar
  44. 44.
    Würtz SO, Schrohl AS, Sorensen NM et al (2005) Tissue inhibitor of metalloproteinases-1 in breast cancer. Endocr Relat Cancer 12(2):215–227PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Florian Schelter
    • 1
  • Martina Grandl
    • 1
  • Bastian Seubert
    • 1
  • Susanne Schaten
    • 1
  • Stephanie Hauser
    • 1
  • Michael Gerg
    • 1
  • Carla Boccaccio
    • 2
  • Paolo Comoglio
    • 2
  • Achim Krüger
    • 1
    Email author
  1. 1.Institut für Experimentelle Onkologie und Therapieforschung des Klinikums rechts der IsarTechnische Universität MünchenMunichGermany
  2. 2.IRCC-Institute for Cancer Research at CandioloUniversità di TorinoCandioloItaly

Personalised recommendations