title: Genetic and pharmacologic inhibition of complement impairs endothelial cell function and ablates ovarian cancer neovascularization.
abstract: Complement activation plays a critical role in controlling inflammatory responses. To assess the role of complement during ovarian cancer progression, we crossed two strains of mice with genetic complement deficiencies with transgenic mice that develop epithelial ovarian cancer (TgMISIIR-TAg). TgMISIIR-TAg mice fully or partially deficient for complement factor 3 (C3) (Tg(+)C3(KO) and Tg(+)C3(HET), respectively) or fully deficient for complement factor C5a receptor (C5aR) (Tg(+)C5aR(KO)) develop either no ovarian tumors or tumors that were small and poorly vascularized compared to wild-type littermates (Tg(+)C3(WT), Tg(+)C5aR(WT)). The percentage of tumor infiltrating immune cells in Tg(+)C3(HET) tumors compared to Tg(+)C3(WT) controls was either similar (macrophages, B cells, myeloid-derived suppressor cells), elevated (effector T cells), or decreased (regulatory T cells). Regardless of these ratios, cytokine production by immune cells taken from Tg(+)C3(HET) tumors was reduced on stimulation compared to Tg(+)C3(WT) controls. Interestingly, CD31(+) endothelial cell (EC) function in angiogenesis was significantly impaired in both C3(KO) and C5aR(KO) mice. Further, using the C5aR antagonist PMX53, tube formation of ECs was shown to be C5a-dependent, possibly through interactions with the VEGF(165) but not VEGF(121) isoform. Finally, the mouse VEGF(164) transcript was underexpressed in C3(KO) livers compare to C3(WT) livers. Thus, we conclude that complement inhibition blocks tumor outgrowth by altering EC function and VEGF(165) expression.
authors.affiliation: Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Selene
authors.initials: S
authors.lastname: Nunez-Cruz
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Gimotty
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Guerra
authors.forename: Denise C
authors.initials: DC
authors.lastname: Connolly
authors.forename: You-Qiang
authors.initials: YQ
authors.lastname: Wu
authors.forename: Robert A
authors.initials: RA
authors.lastname: DeAngelis
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.forename: George
authors.initials: G
authors.lastname: Coukos
authors.forename: Nathalie
authors.initials: N
authors.lastname: Scholler
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology; D003167:Complement Activation / Q000276:immunology; D003176:Complement C3 / Q000172:deficiency; D015936:Complement C5a / Q000037:antagonists & inhibitors / Q000276:immunology; D003165:Complement System Proteins / Q000187:drug effects / Q000235:genetics*; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000276:immunology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D020033:Protein Isoforms; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C438957:AcPhe(ornithine-Pro-cyclohexylamine-Trp-Arg); D003176:Complement C3; D010456:Peptides, Cyclic; D020033:Protein Isoforms; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D015936:Complement C5a; D003165:Complement System Proteins