title: Fcγ receptor-induced soluble vascular endothelial growth factor receptor-1 (VEGFR-1) production inhibits angiogenesis and enhances efficacy of anti-tumor antibodies.
abstract: Monocytes/macrophages are potent mediators of antitumor antibody therapy, where they engage target cells via Fcγ receptors (FcγR). Binding of these cells to opsonized tumor targets elicits cytokine production, phagocytosis, and antibody-mediated cellular cytotoxicity. Here we show for the first time that activation of monocyte FcγR results in the secretion of soluble vascular endothelial growth factor receptor-1 (VEGFR-1/sFlt-1), which serves to antagonize VEGF-mediated angiogenesis and tumor growth. Consistent with this, using a murine solid tumor model of antibody therapy, we show that sFlt-1 is involved in restricting tumor growth. Analyzing the mechanism of induction of sFlt-1, we found that the Erk and PI3K pathways were required for transcription, and NF-κB was required for translation. Upon closer examination of the role of NF-κB, we found that a microRNA, miR181a, negatively regulates FcγR-mediated sFlt-1 production and that NF-κB serves to antagonize this microRNA. Taken together, these results demonstrate a novel and biologically important function of monocytes and macrophages during antibody therapy.
authors.affiliation: From the Department of Internal Medicine.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Justiniano
authors.forename: Saranya
authors.initials: S
authors.lastname: Elavazhagan
authors.forename: Kavin
authors.initials: K
authors.lastname: Fatehchand
authors.forename: Prexy
authors.initials: P
authors.lastname: Shah
authors.forename: Payal
authors.initials: P
authors.lastname: Mehta
authors.forename: Julie M
authors.initials: JM
authors.lastname: Roda
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.forename: Carolyn
authors.initials: C
authors.lastname: Cheney
authors.forename: Erin
authors.initials: E
authors.lastname: Hertlein
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Eubank
authors.forename: Clay
authors.initials: C
authors.lastname: Marsh
authors.forename: Natarajan
authors.initials: N
authors.lastname: Muthusamy
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Butchar
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics*; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic; D017452:Receptors, IgG / Q000378:metabolism*; D015398:Signal Transduction; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
chemical_list: D000912:Antibodies, Neoplasm; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D017452:Receptors, IgG; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: Angiogenesis; FCγ Receptors; MicroRNA; Monocytes; Signal Transduction
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