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Angiogenesis

, 14:235 | Cite as

Neutrophil granulocyte derived MMP-9 is a VEGF independent functional component of the angiogenic switch in pancreatic ductal adenocarcinoma

  • Dirk Bausch
  • Thomas Pausch
  • Tobias Krauss
  • Ulrich Theodor Hopt
  • Carlos Fernandez-del-Castillo
  • Andrew L. Warshaw
  • Sarah P. Thayer
  • Tobias Keck
Original Paper

Abstract

Background

Vascular endothelial growth factor (VEGF) that is secreted by tumor cells plays a key role in angiogenesis. Matrix metalloproteinase 9 (MMP-9) is produced by inflammatory cells, such as stromal granulocytes (PMN), remodels the extracellular matrix and is known to promote angiogenesis indirectly by interacting with VEGF. The aim of this study was to determine the role of PMN-derived MMP-9, its interaction with VEGF, and the efficacy of anti-angiogenic therapy targeting MMP-9 with oral Doxycycline and VEGF with Bevacizumab in pancreatic cancer (PDAC).

Methodology/principal findings

Inhibitors to MMP-9 (Doxycycline) and VEGF (Bevacizumab) were used alone or in combination in an in vitro angiogenesis assay to test their effect on angiogenesis caused by MMP-9, VEGF, PMN and PDAC cells. In an in vivo model of xenografted PDAC, treatment effects after 14 days under monotherapy with oral Doxycycline or Bevacizumab and a combination of both were evaluated.

In vitro, PMN-derived MMP-9 had a direct and strong proangiogenic effect that was independent and additive to PDAC-derived VEGF. Complete inhibition of angiogenesis required the inhibition of VEGF and MMP-9. In vivo, co-localization of MMP-9, PMN and vasculature was observed. MMP inhibition with oral Doxycycline alone resulted in a significant decrease in PDAC growth and mean vascular density comparable to VEGF inhibition alone.

Conclusions/significance

PMN derived MMP-9 acts as a potent, direct and VEGF independent angiogenic factor in the context of PDAC. MMP-9 inhibition is as effective as VEGF inhibition. Targeting MMP-9 in addition to VEGF is therefore likely to be important for successful anti-angiogenic treatment in pancreatic cancer.

Keywords

VEGF MMP-9 Neutrophil granulocyte Pancreatic cancer 

Notes

Acknowledgments

The authors would like to thank Nancy Neyhard, Amy Stirman, Silke Hempel and Bettina Waldvogel for their technical assistance and Andrew Liss for his assistance composing the manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Dirk Bausch
    • 1
  • Thomas Pausch
    • 2
  • Tobias Krauss
    • 3
  • Ulrich Theodor Hopt
    • 1
  • Carlos Fernandez-del-Castillo
    • 4
  • Andrew L. Warshaw
    • 4
  • Sarah P. Thayer
    • 4
  • Tobias Keck
    • 1
  1. 1.Department of General and Visceral SurgeryUniversity of FreiburgFreiburgGermany
  2. 2.Klinik für Allgemein, Viszeral- und TransplantationschirurgieUniversität HeidelbergHeidelbergGermany
  3. 3.Radiologische Universitätsklinik Freiburg i. Br.Freiburg i. Br.Germany
  4. 4.Department of SurgeryMassachusetts General Hospital and Harvard Medical SchoolBostonUSA

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