Ⅰ型神经纤维瘤病相关信号通路及微环境组分异常

Abnormal Signaling Pathways and Microenvironment Components Related to Neurofibromatosis Type Ⅰ

Ⅰ型神经纤维瘤病(neurofibromatosis type 1,NF1)是一种由NF1基因突变导致的常染色体显性遗传病,以多发皮肤咖啡斑和神经纤维瘤为主要特征,国际上针对NF1尚无规范治疗策略。NF 1基因庞大,其编码的神经纤维蛋白(neurofibromin,NF)参与细胞增殖调控,该病发病机制复杂,为药物研发带来较大挑战。在NF1信号通路方面,丝裂原活化蛋白激酶的激酶的激酶/丝裂原活化蛋白激酶的激酶/丝裂原活化蛋白激酶通路(RAF/MEK/ERK)、磷脂酰肌醇3激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白通路(PI3K/AKT/mTOR)、无翅蛋白/β联蛋白通路(WNT/β-catenin)、河马蛋白/转录共激活子/YES相关蛋白通路(HIPPO/TAZ/YAP)等均有研究,其中针对RAF/MEK/ERK通路的MEK1/2抑制剂药物已上市,即司美替尼(selumetinib),用于治疗NF1和不能手术的丛状神经纤维瘤(plexiform neurofibroma,PNF)患者。近年研究发现,NF1肿瘤微环境包括施万细胞(Schwann cells,SCs)及其前体、肥大细胞、巨噬细胞、T细胞、树突状细胞、细胞外基质和周围血管等,对NF1的发生发展发挥不可忽视的作用。现今NF1的治疗方法包括手术切除肿瘤、放射治疗和药物治疗,这些方法均有缺陷,迫切需要从NF1信号通路及肿瘤微环境等方面继续深入探索新的治疗药物。本文主要综述了NF1相关信号通路及肿瘤微环境的研究现状,重点讨论了NF1基因突变引起的信号通路改变以及肿瘤微环境的组分异常,并剖析了NF1疾病可能的发病机制,以期为临床NF1早期诊断、治疗、预防和药物研发提供新的思路。

Neurofibromatosis type 1(NF1)is an autosomal dominant genetic disorder caused by mutations of the NF1 gene,which is characterized by multiple caf-au-lait macules and neurofibromas.There are still no standardized treatment strategies for NF1 internationally.The NF1 gene is large and encodes neurofibromin(NF)that participates in cell proliferation.The disease mechanism is complex,which presents major challenges for drug development.Various signaling pathways including the RAF/MEK/ERK,PI3K/AKT/mTOR,WNT/β-catenin,and HIPPO/TAZ/YAP pathways have been studied in NF1.MEK1/2 inhibitors targeting the RAF/MEK/ERK pathway,such as selumetinib,have been approved for the treatment of NF1 and inoperable plexiform neurofibromas(PNF).Recent studies highlighted the crucial role of the NF1 tumor microenvironment,comprising Schwann cells(SCs)and their precursors,mast cells,macrophages,T cells,dendritic cells,the extracellular matrix,and surrounding blood vessels,in NF1 pathogenesis.Current treatments for NF1 include tumor resection,radiotherapy,and pharmacotherapy,all of which have limitations.There is an urgent need for exploration of novel therapeutic agents targeting NF1 signaling pathways and the tumor microenvironment.This review summarizes the current research progress in NF1-related signaling pathways and the microenvironment components.It specifically highlights the changes of the signaling pathways caused by NF1 gene mutations and the abnormal tumor microenvironment components,and analyzes the possible pathogenesis of NF1 to provide new insights for early diagnosis,treatment,prevention,and drug development in clinical NF1 management.