The importance of nerve microenvironment for schwannoma development

Alexander Schulz, Robert Büttner, Christian Hagel, Stephan L. Baader, Lan Kluwe, Johannes Salamon, Victor Felix Mautner, Thomas Mindos, David B. Parkinson, Jeffrey R. Gehlhausen, D. Wade Clapp, Helen Morrison

Research output: Contribution to journalArticle

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)289-307
Number of pages19
JournalActa Neuropathologica
Volume132
Issue number2
DOIs
StatePublished - Aug 1 2016

    Fingerprint

Keywords

  • Crush injury, tissue inflammation
  • Microenvironment
  • NF2
  • Neurofibromatosis type 2
  • Schwannoma
  • Sciatic nerve
  • Tumor induction

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Schulz, A., Büttner, R., Hagel, C., Baader, S. L., Kluwe, L., Salamon, J., Mautner, V. F., Mindos, T., Parkinson, D. B., Gehlhausen, J. R., Clapp, D. W., & Morrison, H. (2016). The importance of nerve microenvironment for schwannoma development. Acta Neuropathologica, 132(2), 289-307. https://doi.org/10.1007/s00401-016-1583-8