title: Neutrophil granulocyte derived MMP-9 is a VEGF independent functional component of the angiogenic switch in pancreatic ductal adenocarcinoma.
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).
  
  
  RESULTS
  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
  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.
authors: Department of General and Visceral Surgery, University of Freiburg, Germany.
authors: Dirk
authors: D
authors: Bausch
authors: Thomas
authors: T
authors: Pausch
authors: Tobias
authors: T
authors: Krauss
authors: Ulrich Theodor
authors: UT
authors: Hopt
authors: Carlos
authors: C
authors: Fernandez-del-Castillo
authors: Andrew L
authors: AL
authors: Warshaw
authors: Sarah P
authors: SP
authors: Thayer
authors: Tobias
authors: T
authors: Keck
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000068258:Bevacizumab; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004318:Doxycycline / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D009504:Neutrophils; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000900:Anti-Bacterial Agents; D061067:Antibodies, Monoclonal, Humanized; D061965:Matrix Metalloproteinase Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline