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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Chemokines / genetics
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Chemokines / metabolism
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Culture Media, Conditioned / chemistry
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Culture Media, Conditioned / pharmacology
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Disease Models, Animal
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Flow Cytometry
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic*
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism
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Interferon alpha-2
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Interferon-alpha / pharmacology
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Macrophage Colony-Stimulating Factor / genetics
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Macrophage Colony-Stimulating Factor / metabolism
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Macrophages / drug effects
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Macrophages / metabolism*
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Macrophages / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Neurofibroma / drug therapy
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Neurofibroma / genetics*
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Neurofibroma / metabolism
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Neurofibroma / pathology
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Neurofibromin 1 / deficiency
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Neurofibromin 1 / genetics*
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Organ Specificity
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Peripheral Nervous System / drug effects
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Peripheral Nervous System / metabolism
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Peripheral Nervous System / pathology
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Peripheral Nervous System Neoplasms / drug therapy
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Peripheral Nervous System Neoplasms / genetics*
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Peripheral Nervous System Neoplasms / metabolism
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Peripheral Nervous System Neoplasms / pathology
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Polyethylene Glycols / pharmacology
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Primary Cell Culture
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Recombinant Proteins / pharmacology
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Schwann Cells / metabolism*
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Schwann Cells / pathology
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Signal Transduction
Substances
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Chemokines
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Culture Media, Conditioned
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Intercellular Signaling Peptides and Proteins
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Interferon alpha-2
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Interferon-alpha
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Neurofibromin 1
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Recombinant Proteins
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Polyethylene Glycols
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Macrophage Colony-Stimulating Factor
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peginterferon alfa-2b