Pundavela Jay, Hall Ashley, Dinglasan Samantha Anne, Choi Kwangmin, Rizvi Tilat A, Trapnell Bruce C, Wu Jianqiang, Ratner Nancy
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Cancers (Basel). 2025 Mar 6;17(5):905. doi: 10.3390/cancers17050905.
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-β) 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-β and GM-CSFR-α on PNF cells and on macrophages and dendritic cells in the PNF, using the Nf1; DhhCre mouse model of neurofibroma formation. Genetic deletion of GM-CSFR-β in 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-β did 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-β signaling 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周围神经鞘瘤，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-β）是细胞因子GM-CSF、IL-3和IL-5受体的共同组成部分，这些配体具有免疫调节和肿瘤促进作用。在本研究中，我们使用了神经纤维瘤的基因工程小鼠模型。利用Nf1; DhhCre神经纤维瘤形成小鼠模型，我们在PNF细胞以及PNF中的巨噬细胞和树突状细胞上鉴定出了GM-CSFR-β和GM-CSFR-α的表达。在该模型中GM-CSFR-β的基因缺失减少了PNF的数量，这与肿瘤相关的Iba1+巨噬细胞和CD11c+树突状细胞（DC）数量减少有关，而GM-CSFR-α的缺失则没有影响。GM-CSFR-α或GM-CSFR-β的缺失并未改善小鼠的存活率或外周神经中Remak束的结构。肿瘤裂解物的蛋白质组分析显示，受体缺失后多种细胞因子的水平发生了改变，这表明其他细胞因子/趋化因子的代偿作用维持了促进神经纤维瘤的促炎环境。因此，GM-CSFR-β信号通路对神经纤维瘤的形成有一定贡献，显然独立于其配体GM-CSF。
