title: Examining the role of Rac1 in tumor angiogenesis and growth: a clinically relevant RNAi-mediated approach.
abstract: Angiogenesis, the sprouting of new blood vessels from the pre-existing vasculature, is a well established target in anti-cancer therapy. It is thought that the Rho GTPase Rac1 is required during vascular endothelial growth factor (VEGF)-mediated angiogenesis. In the present study, we have used a clinically relevant RNA interference approach to silence Rac1 expression. Human umbilical vein endothelial cells were transiently transfected with non-specific control siRNA (siNS) or Rac1 siRNA (siRac1) using electroporation or Lipofectamine 2000. Functional assays with transfected endothelial cells were performed to determine the effect of Rac1 knockdown on angiogenesis in vitro. Silencing of Rac1 inhibited VEGF-mediated tube formation, cell migration, invasion and proliferation. In addition, treatment with Rac1 siRNA inhibited angiogenesis in an in vivo Matrigel plug assay. Intratumoral injections of siRac1 almost completely inhibited the growth of grafted Neuro2a tumors and reduced tumor angiogenesis. Together, these data indicate that Rac1 is an important regulator of VEGF-mediated angiogenesis. Knockdown of Rac1 may represent an attractive approach to inhibit tumor angiogenesis and growth.
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Vader
authors.forename: R
authors.initials: R
authors.lastname: van der Meel
authors.forename: M H
authors.initials: MH
authors.lastname: Symons
authors.forename: M H A M
authors.initials: MH
authors.lastname: Fens
authors.forename: E
authors.initials: E
authors.lastname: Pieters
authors.forename: K J
authors.initials: KJ
authors.lastname: Wilschut
authors.forename: G
authors.initials: G
authors.lastname: Storm
authors.forename: M
authors.initials: M
authors.lastname: Jarzabek
authors.forename: W M
authors.initials: WM
authors.lastname: Gallagher
authors.forename: R M
authors.initials: RM
authors.lastname: Schiffelers
authors.forename: A T
authors.initials: AT
authors.lastname: Byrne
mesh_terms: D000704:Analysis of Variance; D001483:Base Sequence; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen; D004338:Drug Combinations; D018274:Electroporation; D006801:Humans; D007797:Laminin; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011509:Proteoglycans; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015531:Radioimmunoprecipitation Assay; D014162:Transfection; D014471:Umbilical Veins / Q000166:cytology; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; C107953:RAC1 protein, human; D034741:RNA, Small Interfering; C059485:matrigel; D003094:Collagen; D020830:rac1 GTP-Binding Protein