title: Inhibition of cyclo-oxygenase 2 reduces tumor metastasis and inflammatory signaling during blockade of vascular endothelial growth factor.
abstract: Vascular endothelial growth factor (VEGF) blockade is an effective therapy for human cancer, yet virtually all neoplasms resume primary tumor growth or metastasize during therapy. Mechanisms of progression have been proposed to include genes that control vascular remodeling and are elicited by hypoperfusion, such as the inducible enzyme cyclooxygenase-2 (COX-2). We have previously shown that COX-2 inhibition by the celecoxib analog SC236 attenuates perivascular stromal cell recruitment and tumor growth. We therefore examined the effect of combined SC236 and VEGF blockade, using the metastasizing orthotopic SKNEP1 model of pediatric cancer. Combined treatment perturbed tumor vessel remodeling and macrophage recruitment, but did not further limit primary tumor growth as compared to VEGF blockade alone. However, combining SC236 and VEGF inhibition significantly reduced the incidence of lung metastasis, suggesting a distinct effect on prometastatic mechanisms. We found that SC236 limited tumor cell viability and migration in vitro, with effects enhanced by hypoxia, but did not change tumor proliferation or matrix metalloproteinase expression in vivo. Gene set expression analysis (GSEA) indicated that the addition of SC236 to VEGF inhibition significantly reduced expression of gene sets linked to macrophage mobilization. Perivascular recruitment of macrophages induced by VEGF blockade was disrupted in tumors treated with combined VEGF- and COX-2-inhibition. Collectively, these findings suggest that during VEGF blockade COX-2 may restrict metastasis by limiting both prometastatic behaviors in individual tumor cells and mobilization of macrophages to the tumor vasculature.
authors: Department of Surgery, Cincinnati Children's Hospital and Medical Center, 3333 Burnet Ave, Cincinnati, 45229-3039, USA.
authors: Jason C
authors: JC
authors: Fisher
authors: Department of Surgery, College of Physicians and Surgeons of Columbia University, 630 W. 168th St., New York, New York 10032, USA.
authors: Jeffrey W
authors: JW
authors: Gander
authors: Department of Surgery, College of Physicians and Surgeons of Columbia University, 630 W. 168th St., New York, New York 10032, USA.
authors: Mary Jo
authors: MJ
authors: Haley
authors: Department of Pediatrics, College of Physicians and Surgeons of Columbia University, 630 W. 168th St., New York, New York 10032, USA.
authors: Sonia L
authors: SL
authors: Hernandez
authors: Department of Surgery, College of Physicians and Surgeons of Columbia University, 630 W. 168th St., New York, New York 10032, USA.
authors: Jianzhong
authors: J
authors: Huang
authors: Department of Surgery, College of Physicians and Surgeons of Columbia University, 630 W. 168th St., New York, New York 10032, USA.
authors: Yan-Jung
authors: YJ
authors: Chang
authors: Department of Surgery, College of Physicians and Surgeons of Columbia University, 630 W. 168th St., New York, New York 10032, USA.
authors: Tessa B
authors: TB
authors: Johung
authors: Center for Computational Biology and Bioinformatics, College of Physicians and Surgeons of Columbia University, 1130 St. Nicholas Ave, New York, New York 10032, USA.
authors: Paolo
authors: P
authors: Guarnieri
authors: Department of Pathology, College of Physicians and Surgeons of Columbia University, 630 W. 168th St., New York, New York 10032, USA.
authors: Kathleen
authors: K
authors: O'Toole
authors: Department of Surgery, College of Physicians and Surgeons of Columbia University, 630 W. 168th St., New York, New York 10032, USA.|Department of Pathology, College of Physicians and Surgeons of Columbia University, 630 W. 168th St., New York, New York 10032, USA.|Department of Pediatrics, College of Physicians and Surgeons of Columbia University, 630 W. 168th St., New York, New York 10032, USA.
authors: Darrell J
authors: DJ
authors: Yamashiro
authors: Department of Surgery, College of Physicians and Surgeons of Columbia University, 630 W. 168th St., New York, New York 10032, USA.
authors: Jessica J
authors: JJ
authors: Kandel