title: Inhibition of cyclooxygenase-2 disrupts tumor vascular mural cell recruitment and survival signaling.
abstract: Much evidence supports an important role for the inducible enzyme cyclooxygenase-2 (COX-2) in tumor angiogenesis. Previous studies have focused on the role of COX-2 in stimulating endothelial proliferation, with blockade of this enzyme impairing endothelial homeostasis. However, recent data suggest that COX-2 also regulates molecules implicated in endothelial trafficking with pericytes/vascular mural cells (VMC), an interaction crucial to vessel stability. We investigated the role of COX-2 in vascular assembly by testing the effect of the specific COX-2 inhibitor SC-236 in an orthotopic xenograft model of human Wilms' tumor. Tumor growth was significantly suppressed by SC-236 (78% at day 28, 55% at day 35). Perfusion studies and immunostaining showed a marked decrease in vasculature, particularly in small vessels. Specifically, SC-236 inhibited participation of VMC in xenograft vessels. SC-236-treated tumors developed segmentally dilated, architecturally erratic tumor vessels with decreased nascent pericytes and scant mature VMC. Although vascular endothelial growth factor expression was unchanged, expression of the chemokine receptor CXCR4 was decreased in tumor vessels, consistent with defective homing of vascular progenitor cells. Vascular expression of phosphorylated platelet-derived growth factor receptor-beta was also diminished, indicating impaired VMC-endothelial trafficking. Consistent with the key role of this interaction in vessel homeostasis, vascular cells in SC-236-treated tumors displayed markedly diminished phosphorylated Akt, indicating disrupted survival signaling. These results show that SC-236 causes defective vascular assembly by attenuating incorporation of VMC into tumor vessels, impairing endothelial survival, and raise the possibility that blockade of COX-2 may provide therapeutic synergies with antiangiogenic molecules that more selectively target endothelial cells.
authors.affiliation: Department of Pediatrics, College of Physicians and Surgeons of Columbia University, New York, New York, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Lee
authors.forename: Jason
authors.initials: J
authors.lastname: Frischer
authors.forename: Anna
authors.initials: A
authors.lastname: Serur
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Huang
authors.forename: Jae-O
authors.initials: JO
authors.lastname: Bae
authors.forename: Zev Noah
authors.initials: ZN
authors.lastname: Kornfield
authors.forename: Lucy
authors.initials: L
authors.lastname: Eljuga
authors.forename: Carrie J
authors.initials: CJ
authors.lastname: Shawber
authors.forename: Nikki
authors.initials: N
authors.lastname: Feirt
authors.forename: Mahesh
authors.initials: M
authors.lastname: Mansukhani
authors.forename: Diana
authors.initials: D
authors.lastname: Stempak
authors.forename: Sylvain
authors.initials: S
authors.lastname: Baruchel
authors.forename: Julia
authors.initials: J
authors.lastname: Glade Bender
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Kandel
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: Yamashiro
mesh_terms: D000818:Animals; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000172:deficiency; D013449:Sulfonamides / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D009396:Wilms Tumor / Q000098:blood supply* / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000096926:Benzenesulfonamides
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D020574:Proto-Oncogene Proteins c-sis; D011720:Pyrazoles; D020797:Receptor, Platelet-Derived Growth Factor beta; D019718:Receptors, CXCR4; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides