Plexiform neurofibroma (PNF) is an immune cell-rich peripheral nerve sheath tumor that develops primarily in individuals with Neurofibromatosis Type 1 (NF1). Granulocyte-macrophage colony stimulating factor receptor-β (GM-CSFR-βc) is a shared component of receptors for the cytokines GM-CSF, IL-3, and IL-5, ligands with immunomodulatory and tumor promoting roles. In the present study, we use genetically engineered mouse model of neurofibroma. We identified the expression of GM-CSFR-βcand GM-CSFR-α on PNF cells and on macrophages and dendritic cells in the PNF, using the Nf1f/f; DhhCre mouse model of neurofibroma formation. Genetic deletion of GM-CSFR-βcin this model reduced the number of PNFs, which was associated with decreased numbers of tumor-associated Iba1+ macrophages and CD11c+ dendritic cells (DC), while loss of GM-CSFR-α had no effect. Deletion of GM-CSFR-α or GM-CSFR-βcdid not improve mouse survival or the structure of Remak bundles in peripheral nerves. Proteome analysis of tumor lysates showed altered levels of numerous cytokines after receptor loss, suggesting that the compensatory effects of other cyto/chemokines maintain a proinflammatory environment promoting neurofibroma. Thus, GM-CSFR-βcsignaling contributes modestly to neurofibroma formation, apparently independently of its ligand GM-CSF.
丛状神经纤维瘤（PNF）是一种富含免疫细胞的外周神经鞘肿瘤，主要发生于1型神经纤维瘤病（NF1）患者。粒细胞-巨噬细胞集落刺激因子受体-β（GM-CSFR-βc）是细胞因子GM-CSF、IL-3和IL-5受体的共同组分，这些配体具有免疫调节和肿瘤促进作用。本研究采用基因工程小鼠神经纤维瘤模型，通过Nf1f/f; DhhCre神经纤维瘤形成小鼠模型，发现PNF细胞及其内部的巨噬细胞和树突状细胞均表达GM-CSFR-βc和GM-CSFR-α。在该模型中敲除GM-CSFR-βc可减少PNF数量，同时伴随肿瘤相关Iba1+巨噬细胞和CD11c+树突状细胞数量下降，而GM-CSFR-α缺失则无此效应。敲除GM-CSFR-α或GM-CSFR-βc均未改善小鼠生存率或外周神经Remak束结构。肿瘤裂解液的蛋白质组学分析显示，受体缺失后多种细胞因子水平发生改变，提示其他细胞因子/趋化因子的代偿效应维持了促炎微环境，从而促进神经纤维瘤形成。因此，GM-CSFR-βc信号通路对神经纤维瘤形成具有适度促进作用，且该作用明显不依赖于其配体GM-CSF。
肿瘤(癌症)患者之家