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.
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.
Authors: Christina L Roland; Sean P Dineen; Jason E Toombs; Juliet G Carbon; C Wayne Smith; Rolf A Brekken; Carlton C Barnett Journal: Exp Biol Med (Maywood) Date: 2010-02
Authors: Lukas J A C Hawinkels; Kim Zuidwijk; Hein W Verspaget; Eveline S M de Jonge-Muller; Wim van Duijn; Valérie Ferreira; Ruud D Fontijn; Guido David; Daniel W Hommes; Cornelis B H W Lamers; Cornelis F M Sier Journal: Eur J Cancer Date: 2008-08-06 Impact factor: 9.162
Authors: Veronica C Ardi; Tatyana A Kupriyanova; Elena I Deryugina; James P Quigley Journal: Proc Natl Acad Sci U S A Date: 2007-12-11 Impact factor: 11.205
Authors: Andrew H Ko; Elizabeth Dito; Brian Schillinger; Alan P Venook; Zhidong Xu; Emily K Bergsland; Derrick Wong; Janet Scott; Jimmy Hwang; Margaret A Tempero Journal: Invest New Drugs Date: 2008-04-01 Impact factor: 3.850
Authors: John M L Ebos; Christina R Lee; William Cruz-Munoz; Georg A Bjarnason; James G Christensen; Robert S Kerbel Journal: Cancer Cell Date: 2009-03-03 Impact factor: 31.743
Authors: Eric Van Cutsem; Walter L Vervenne; Jaafar Bennouna; Yves Humblet; Sharlene Gill; Jean-Luc Van Laethem; Chris Verslype; Werner Scheithauer; Aijing Shang; Jan Cosaert; Malcolm J Moore Journal: J Clin Oncol Date: 2009-03-23 Impact factor: 44.544
Authors: Ewa Zajac; Bernhard Schweighofer; Tatyana A Kupriyanova; Anna Juncker-Jensen; Petra Minder; James P Quigley; Elena I Deryugina Journal: Blood Date: 2013-10-30 Impact factor: 22.113
Authors: Claudia Schrimpf; Cuiyan Xin; Gabriella Campanholle; Sean E Gill; William Stallcup; Shuei-Liong Lin; George E Davis; Sina A Gharib; Benjamin D Humphreys; Jeremy S Duffield Journal: J Am Soc Nephrol Date: 2012-03-01 Impact factor: 10.121