Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
J Clin Invest. 2018 Jul 2;128(7):2848-2861. doi: 10.1172/JCI99424. Epub 2018 May 21.
Neurofibromatosis type 1 associates with multiple neoplasms, and the Schwann cell tumor neurofibroma is the most prevalent. A hallmark feature of neurofibroma is mast cell infiltration, which is recruited by chemoattractant stem cell factor (SCF) and has been suggested to sustain neurofibroma tumorigenesis. In the present study, we use new, genetically engineered Scf mice to decipher the contributions of tumor-derived SCF and mast cells to neurofibroma development. We demonstrate that mast cell infiltration is dependent on SCF from tumor Schwann cells. However, removal of mast cells by depleting the main SCF source only slightly affects neurofibroma progression. Other inflammation signatures show that all neurofibromas are associated with high levels of macrophages regardless of Scf status. These findings suggest an active inflammation in neurofibromas and partly explain why mast cell removal alone is not sufficient to relieve tumor burden in this experimental neurofibroma model. Furthermore, we show that plexiform neurofibromas are highly associated with injury-prone spinal nerves that are close to flexible vertebras. In summary, our study details the role of inflammation in neurofibromagenesis. Our data indicate that prevention of inflammation and possibly also nerve injury at the observed tumor locations are therapeutic approaches for neurofibroma prophylaxis and that such treatment should be explored.
神经纤维瘤病 1 型与多种肿瘤相关，而雪旺氏细胞瘤神经纤维瘤是最常见的。神经纤维瘤的一个显著特征是肥大细胞浸润，它被趋化性干细胞因子（SCF）募集，并被认为维持神经纤维瘤的肿瘤发生。在本研究中，我们使用新的基因工程 Scf 小鼠来阐明肿瘤来源的 SCF 和肥大细胞对神经纤维瘤发展的贡献。我们证明，肥大细胞浸润依赖于肿瘤雪旺氏细胞的 SCF。然而，通过耗尽主要的 SCF 来源来去除肥大细胞，仅对神经纤维瘤的进展有轻微影响。其他炎症特征表明，所有神经纤维瘤都与高水平的巨噬细胞有关，而与 Scf 状态无关。这些发现表明神经纤维瘤中存在活跃的炎症，部分解释了为什么仅去除肥大细胞不足以减轻这种实验性神经纤维瘤模型中的肿瘤负担。此外，我们还表明，丛状神经纤维瘤与易受伤的脊柱神经高度相关，这些神经靠近灵活的脊椎。总之，我们的研究详细说明了炎症在神经纤维瘤发生中的作用。我们的数据表明，预防炎症和可能在观察到的肿瘤部位的神经损伤是预防神经纤维瘤的治疗方法，应该对此进行探索。
