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.

中文翻译：

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神经微环境对神经鞘瘤发展的重要性。

神经鞘瘤主要是由 Nf2 基因失活引起的良性神经鞘瘤。目前，由于缺乏有效的药物，治疗选择主要限于手术切除肿瘤。尽管对 Nf2 基因功能的机械理解有所进步，但到目前为止，它主要局限于雪旺细胞内在事件。决定雪旺氏细胞在神经鞘瘤发展方面的行为的细胞外线索仍然未知。在这里，我们展示了促肿瘤微环境对雪旺氏细胞的影响，其中改变的轴突微环境与损伤信号一起有助于持续的再生雪旺氏细胞反应，促进神经鞘瘤的发展。特别是在坐骨神经挤压伤后的基因工程小鼠中，我们在雪旺细胞中具有纯合 nf2 基因缺失的小鼠以及在雪旺细胞和轴突中具有杂合 nf2 基因敲除的动物中发现了肉眼可见的神经肿胀。然而，模拟患者的神经鞘瘤只能在雪旺细胞和轴突中结合杂合 nf2 敲除的动物中诱发。我们将严重的髓鞘再生缺陷和肿瘤组织中持续存在的巨噬细胞确定为主要异常。引人注目的是，在这种疾病模型中，用中等剂量阿司匹林治疗神经挤压损伤后的肿瘤发展小鼠显着降低了神经鞘瘤的进展。我们的研究结果表明神经鞘瘤形成的多因素概念 - 强调轴突因子和机械神经刺激作为神经鞘瘤发展的好发部位。此外，