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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1583-8) contains supplementary material, which is available to authorized users.

Inflammaging impairs peripheral nerve maintenance and regeneration

“…Acetylsalicylic acid (ASA) inhibits mammalian innate immune responses (Morris et al, 2009) and decreases macrophage infiltration in sciatic nerves (Schulz et al, 2016). To test whether suppression of the injury‐induced, hyperinflammatory response in old mice by ASA could improve peripheral nerve regeneration, we set up a four‐week treatment protocol using two cohorts of old mice (Figure 4a).…”

“…Acetylsalicylic acid (ASA), shown to decrease the macrophage number in sciatic nerves (Schulz et al, 2016), was the drug chosen to assess an anti‐inflammatory therapy for old mice subjected to peripheral nerve injury—reasoning that repressing injury‐induced abnormal hyperinflammatory responses should augment nerve recovery in old mice. Following crush injury, accelerated functional recovery, accompanied by advanced remyelination and decreased macrophage appearance, was observed in ASA‐treated mice (Figure 4).…”

“…Unilateral injuries of sciatic nerves were performed with minimal invasion, as described previously (Schulz et al, 2016). For details see Supporting Information Appendix S1.…”

“…Application of ASA (Sigma‐Aldrich, St. Louis, MO, USA), 10 mg per kg body weight, was performed as previously described (Schulz et al, 2016). Recombinant murine Eotaxin/CCL11 (PeproTech, Hamburg, Germany) was injected intraperitoneally at 10 µg per kg body weight from one week before until four weeks after crush injury.…”

Intramural schwannoma involving a vein

“…There are several papers relating previous trauma with development of a subsequent schwannomas in varied anatomical areas . Most interesting, animal models show that a persistent environment promoting Schwann cell regeneration can contribute to the development of schwannomas . Specifically, crush injuries on nerves were able to induce schwannomas, albeit in animals with already a combined heterozygous nf2 knockout in Schwann cells and axons …”