title: An inflammatory gene signature distinguishes neurofibroma Schwann cells and macrophages from cells in the normal peripheral nervous system.
abstract: Neurofibromas are benign peripheral nerve tumors driven by NF1 loss in Schwann cells (SCs). Macrophages are abundant in neurofibromas, and macrophage targeted interventions may have therapeutic potential in these tumors. We generated gene expression data from fluorescence-activated cell sorted (FACS) SCs and macrophages from wild-type and mutant nerve and neurofibroma to identify candidate pathways involved in SC-macrophage cross-talk. While in 1-month-old Nf1 mutant nerve neither SCs nor macrophages significantly differed from their normal counterparts, both macrophages and SCs showed significantly altered cytokine gene expression in neurofibromas. Computationally reconstructed SC-macrophage molecular networks were enriched for inflammation-associated pathways. We verified that neurofibroma SC conditioned medium contains macrophage chemo-attractants including colony stimulation factor 1 (CSF1). Network analysis confirmed previously implicated pathways and predict novel paracrine and autocrine loops involving cytokines, chemokines, and growth factors. Network analysis also predicted a central role for decreased type-I interferon signaling. We validated type-I interferon expression in neurofibroma by protein profiling, and show that treatment of neurofibroma-bearing mice with polyethylene glycolyated (PEGylated) type-I interferon-α2b reduces the expression of many cytokines overexpressed in neurofibroma. These studies reveal numerous potential targetable interactions between Nf1 mutant SCs and macrophages for further analyses.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Kwangmin
authors.initials: K
authors.lastname: Choi
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Kakajan
authors.initials: K
authors.lastname: Komurov
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Fletcher
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Edwin
authors.initials: E
authors.lastname: Jousma
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA.|Hoxworth Blood Center, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Cancelas
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Wu
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Ratner
mesh_terms: D000818:Animals; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009455:Neurofibroma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025542:Neurofibromin 1 / Q000172:deficiency / Q000235:genetics*; D009928:Organ Specificity; D017933:Peripheral Nervous System / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010524:Peripheral Nervous System Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011092:Polyethylene Glycols / Q000494:pharmacology; D061251:Primary Cell Culture; D011994:Recombinant Proteins / Q000494:pharmacology; D012583:Schwann Cells / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D018925:Chemokines; D017077:Culture Media, Conditioned; D036341:Intercellular Signaling Peptides and Proteins; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D025542:Neurofibromin 1; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D016173:Macrophage Colony-Stimulating Factor; C417083:peginterferon alfa-2b