Cyclooxygenase-2 blockade can improve efficacy of VEGF-targeting drugs
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Cyclooxygenase-2 blockade can improve efficacy of VEGF-targeting drugs. / Ben-Batalla, Isabel; Cubas-Cordova, Miguel; Udonta, Florian; Wroblewski, Mark; Waizenegger, Jonas S; Janning, Melanie; Sawall, Stefanie; Gensch, Victoria; Zhao, Lin; Martinez-Zubiaurre, Iñigo; Riecken, Kristoffer; Fehse, Boris; Pantel, Klaus; Bokemeyer, Carsten; Loges, Sonja.
in: ONCOTARGET, Jahrgang 6, Nr. 8, 20.03.2015, S. 6341-58.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Cyclooxygenase-2 blockade can improve efficacy of VEGF-targeting drugs
AU - Ben-Batalla, Isabel
AU - Cubas-Cordova, Miguel
AU - Udonta, Florian
AU - Wroblewski, Mark
AU - Waizenegger, Jonas S
AU - Janning, Melanie
AU - Sawall, Stefanie
AU - Gensch, Victoria
AU - Zhao, Lin
AU - Martinez-Zubiaurre, Iñigo
AU - Riecken, Kristoffer
AU - Fehse, Boris
AU - Pantel, Klaus
AU - Bokemeyer, Carsten
AU - Loges, Sonja
PY - 2015/3/20
Y1 - 2015/3/20
N2 - 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.
AB - 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.
U2 - 10.18632/oncotarget.3437
DO - 10.18632/oncotarget.3437
M3 - SCORING: Journal article
C2 - 25849942
VL - 6
SP - 6341
EP - 6358
JO - ONCOTARGET
JF - ONCOTARGET
SN - 1949-2553
IS - 8
ER -
