title: SiRNA-mediated inhibition of vascular endothelial growth factor severely limits tumor resistance to antiangiogenic thrombospondin-1 and slows tumor vascularization and growth.
abstract: In the past few years, several laboratories have developed antiangiogenic molecules that starve tumors by targeting their vasculature and we have shown that, when produced in tumors, the antiangiogenic molecule thrombospondin-1 (TSP1) reduces the vascularization and delays tumor onset. Yet over time, tumor cells producing active TSP1 do eventually form exponentially growing tumors. These tumors are composed of cells secreting unusually high amounts of the angiogenic stimulator vascular endothelial growth factor (VEGF) that are sufficient to overcome the inhibitory TSP1. Here, we use short double-stranded RNA (siRNA) to trigger RNA interference and thereby impair the synthesis of VEGF and ask if this inability to produce VEGF prevents the development of TSP1 resistance. Systemic in vivo administration of crude anti-VEGF siRNA reduced the growth of unaltered fibrosarcoma tumor cells, and when the anti-VEGF siRNA was expressed from tumor cells themselves, such inhibition was synergistic with the inhibitory effects derived from TSP1 secretion by the tumor cells. Anti-VEGF siRNA delayed the emergence of TSP1-resistant tumors and strikingly reduced their subsequent growth rate.
authors.affiliation: CNRS UPR 9079, 94801 Villejuif, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Filleur
authors.forename: Aurélie
authors.initials: A
authors.lastname: Courtin
authors.forename: Slimane
authors.initials: S
authors.lastname: Ait-Si-Ali
authors.forename: Julien
authors.initials: J
authors.lastname: Guglielmi
authors.forename: Carole
authors.initials: C
authors.lastname: Merle
authors.forename: Annick
authors.initials: A
authors.lastname: Harel-Bellan
authors.forename: Philippe
authors.initials: P
authors.lastname: Clézardin
authors.forename: Florence
authors.initials: F
authors.lastname: Cabon
mesh_terms: D000818:Animals; D002455:Cell Division / Q000235:genetics; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005354:Fibrosarcoma / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D008222:Lymphokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D034741:RNA, Small Interfering / Q000235:genetics*; D051381:Rats; D019700:Thrombospondin 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D034741:RNA, Small Interfering; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors