The importance of nerve microenvironment for schwannoma development

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

Unexpected long-range edge-to-forest interior environmental gradients

We examined the relationships between distance-to-edge and environmental factors inferred from mean plant indicator values across large distance-to-edge and patch size gradients. Floristic composition, landscape metrics and site variables (climate, soil and forest management) were collected on 19,989 plots in 1,801 forest patches in Northern France using the French National Forest Inventory. Statistical models were applied to mean plant indicator values (MIV) from Ellenberg and Ecoplant databases for soil pH, soil nitrogen (N), soil humidity (F), light (L) and air temperature (Ta) using distance-to-edge and forest patch size as predictors. The five mean indicator values significantly varied with distance-to-edge and MIV pH, N and Ta decreased over distances in excess of 500 m. Consistent very long edge-to-interior gradients were also detected for site variables. The distance-to-edge effect remained significant after controlling for site differences, especially for MIV pH and N. Significant edge-to-core gradients of MIV were detected over much larger ranges than previously recognised. Neither the presence of an ecological boundary between forest and the surrounding matrix, nor microclimate, soil or forest management heterogeneity within forest patches can fully explain this long edge-to-interior gradient observed in MIV. Two hypotheses are discussed for MIV pH and N: (1) soil eutrophication, due to atmospheric N deposition, which could occur deeper into forest-cores than previously acknowledged; (2) land use legacies, as the periphery of ancient forests is more often occupied by recent forests where former agricultural practices have irreversibly modified topsoil properties. Land use history data would help identify the drivers underlying these long-range edge gradients