title: Effect of VEGF and VEGF Trap on vascular endothelial cell signaling in tumors.
abstract: Vascular endothelial growth factor (VEGF) A is a major promoter of tumor angiogenesis and a prime target of antiangiogenic cancer therapy. To examine whether endothelial cell signaling might provide histological biomarkers of angiogenesis and VEGF activity in vivo, normal mouse organs and multiple tumor models were studied immunohistochemically for endothelial expression of activated ERK, STAT3, and AKT. Phospho(p)-ERK and p-STAT3 expression was negligible in the endothelia of normal organs but was significantly elevated in tumor endothelium. p-AKT was present at significant and comparable levels in both tumor and normal endothelia. In K1735 tumors induced to express more VEGF, endothelial p-ERK, p-STAT3 and p-AKT increased accompanied by signs of accelerated angiogenesis. Treatment of K1735 and Colo-205 tumors with the VEGF inhibitor, VEGF Trap (aflibercept), decreased tumor endothelial p-ERK, p-STAT3 and p-AKT expression accompanied by signs of antiangiogenic effect. These results show that endothelial p-ERK and p-STAT3 (but not p-AKT) distinguish tumor from normal vessels and that the presence of these two signaling intermediates may be useful indicators of tumor angiogenic activity and angiogenesis inhibition by VEGF antagonist.
authors.affiliation: Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Wiem
authors.initials: W
authors.lastname: Lassoued
authors.forename: Danielle
authors.initials: D
authors.lastname: Murphy
authors.forename: Jeff
authors.initials: J
authors.lastname: Tsai
authors.forename: Ridha
authors.initials: R
authors.lastname: Oueslati
authors.forename: Gavin
authors.initials: G
authors.lastname: Thurston
authors.forename: William M F
authors.initials: WM
authors.lastname: Lee
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D004318:Doxycycline / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor; D051058:Oncogene Protein v-akt; D020928:Mitogen-Activated Protein Kinases; D004318:Doxycycline