title: The importance of nerve microenvironment for schwannoma development.
abstract: Schwannomas are predominantly benign nerve sheath neoplasms caused by Nf2 gene inactivation. Presently, treatment options are mainly limited to surgical tumor resection due to the lack of effective pharmacological drugs. Although the mechanistic understanding of Nf2 gene function has advanced, it has so far been primarily restricted to Schwann cell-intrinsic events. Extracellular cues determining Schwann cell behavior with regard to schwannoma development remain unknown. Here we show pro-tumourigenic microenvironmental effects on Schwann cells where an altered axonal microenvironment in cooperation with injury signals contribute to a persistent regenerative Schwann cell response promoting schwannoma development. Specifically in genetically engineered mice following crush injuries on sciatic nerves, we found macroscopic nerve swellings in mice with homozygous nf2 gene deletion in Schwann cells and in animals with heterozygous nf2 knockout in both Schwann cells and axons. However, patient-mimicking schwannomas could only be provoked in animals with combined heterozygous nf2 knockout in Schwann cells and axons. We identified a severe re-myelination defect and sustained macrophage presence in the tumor tissue as major abnormalities. Strikingly, treatment of tumor-developing mice after nerve crush injury with medium-dose aspirin significantly decreased schwannoma progression in this disease model. Our results suggest a multifactorial concept for schwannoma formation-emphasizing axonal factors and mechanical nerve irritation as predilection site for schwannoma development. Furthermore, we provide evidence supporting the potential efficacy of anti-inflammatory drugs in the treatment of schwannomas.
authors.affiliation: Leibniz Institute on Aging, Fritz Lipmann Institute, Beutenbergstrasse 11, 07745, Jena, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schulz
authors.affiliation: Leibniz Institute on Aging, Fritz Lipmann Institute, Beutenbergstrasse 11, 07745, Jena, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Büttner
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hagel
authors.affiliation: Institute of Anatomy, Anatomy and Cell Biology, University of Bonn, 53115, Bonn, Germany.
authors.forename: Stephan L
authors.initials: SL
authors.lastname: Baader
authors.affiliation: Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.|Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
authors.forename: Lan
authors.initials: L
authors.lastname: Kluwe
authors.affiliation: Department of Diagnostic and Interventional Radiology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Salamon
authors.affiliation: Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
authors.forename: Victor-Felix
authors.initials: VF
authors.lastname: Mautner
authors.affiliation: Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, Devon, PL6 8BU, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mindos
authors.affiliation: Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, Devon, PL6 8BU, UK.
authors.forename: David B
authors.initials: DB
authors.lastname: Parkinson
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research Department of Biochemistry, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Gehlhausen
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research Department of Biochemistry, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
authors.forename: D Wade
authors.initials: DW
authors.lastname: Clapp
authors.affiliation: Leibniz Institute on Aging, Fritz Lipmann Institute, Beutenbergstrasse 11, 07745, Jena, Germany. helen.morrison@leibniz-fli.de.
authors.forename: Helen
authors.initials: H
authors.lastname: Morrison
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology*; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000473:pathology; D009442:Neurilemmoma / Q000235:genetics / Q000473:pathology*; D016518:Neurofibromatosis 2 / Q000235:genetics; D012583:Schwann Cells / Q000473:pathology*; D012584:Sciatic Nerve / Q000473:pathology*; D059016:Tumor Microenvironment / Q000235:genetics / Q000502:physiology*
keywords: Crush injury, tissue inflammation; Microenvironment; NF2; Neurofibromatosis type 2; Schwannoma; Sciatic nerve; Tumor induction