Cyclooxygenase-2 blockade can improve efficacy of VEGF-targeting drugs
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Isabel Ben-Batalla1,2, Miguel Cubas-Cordova1,2, Florian Udonta1,2, Mark Wroblewski1,2, Jonas S. Waizenegger1,2, Melanie Janning1,2, Stefanie Sawall1,2, Victoria Gensch1,2, Lin Zhao1,2, Iñigo Martinez-Zubiaurre3, Kristoffer Riecken4, Boris Fehse4, Klaus Pantel2, Carsten Bokemeyer1 and Sonja Loges1,2
1 Department of Hematology and Oncology, BMT with Section of Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
2 Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
3 Department of Clinical Medicine, The Arctic University of Norway, Tromsø, Norway
4 Research Department Cell and Gene Therapy, Clinic for Stem Cell Transplantation, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Sonja Loges, email:
Keywords: breast cancer, anti-angiogenic therapies, Cox-2, CAFs
Received: September 28, 2014 Accepted: January 21, 2015 Published: January 31, 2015
Anti-angiogenic therapies were approved for different cancers. However, significant primary and secondary resistance hampers efficacy in several tumor types including breast cancer. Thus, we need to develop clinically applicable strategies to enhance efficacy of anti-angiogenic drugs.
We report that anti-angiogenic therapies can induce upregulation of cyclooxygenase-2 (Cox-2) and of its product prostaglandin E2 (PGE2) in breast cancer models. Upon Cox-2 inhibition PGE2 levels were normalized and efficacy of anti-vascular endothelial growth factor receptor 2 (anti-VEGFR-2) antibodies and sunitinib was enhanced. Interestingly, both treatments exerted additive anti-angiogenic effects. Following Cox-2 inhibition, we observed reduced infiltration of tumors with cancer-associated fibroblasts (CAFs) and lower levels of pro-angiogenic factors active besides the VEGF axis including hepatocyte growth factor (HGF) and basic fibroblast growth factor (FGF2). Mechanistic studies indicated that Cox-2 inhibition reduced PGE2-induced migration and proliferation of CAFs via inhibiting phosphorylation of Akt.
Hence, Cox-2 inhibition can increase efficacy of anti-angiogenic treatments and our findings might pave the road for clinical investigations of concomitant blockade of Cox-2 and VEGF-signaling.
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