Division of Neuropathology, Department of Pathology, University of Alabama at Birmingham, 1720 Seventh Avenue South, SC930G3, Birmingham, AL 35294-0017, USA.
Acta Neuropathol. 2012 Mar;123(3):321-48. doi: 10.1007/s00401-011-0928-6. Epub 2011 Dec 11.
Neurofibromas, schwannomas and malignant peripheral nerve sheath tumors (MPNSTs) all arise from the Schwann cell lineage. Despite their common origin, these tumor types have distinct pathologies and clinical behaviors; a growing body of evidence indicates that they also arise via distinct pathogenic mechanisms. Identification of the genes that are mutated in genetic diseases characterized by the development of either neurofibromas and MPNSTs [neurofibromatosis type 1 (NF1)] or schwannomas [neurofibromatosis type 2 (NF2), schwannomatosis and Carney complex type 1] has greatly advanced our understanding of these mechanisms. The development of genetically engineered mice with ablation of NF1, NF2, SMARCB1/INI1 or PRKAR1A has confirmed the key role these genes play in peripheral nerve sheath tumorigenesis. Establishing the functions of the NF1, NF2, SMARCB1/INI1 and PRKAR1A gene products has led to the identification of key cytoplasmic signaling pathways promoting Schwann cell neoplasia and identified new therapeutic targets. Analyses of human neoplasms and genetically engineered mouse models have established that interactions with other tumor suppressors such as TP53 and CDKN2A promote neurofibroma-MPNST progression and indicate that intratumoral interactions between neoplastic and non-neoplastic cell types play an essential role in peripheral nerve sheath tumorigenesis. Recent advances have also provided new insights into the identity of the neural crest-derived populations that give rise to different types of peripheral nerve sheath tumors. Based on these findings, we now have an initial outline of the molecular mechanisms driving the pathogenesis of neurofibromas, MPNSTs and schwannomas. However, this improved understanding in turn raises a host of intriguing new questions.
神经纤维瘤、施万细胞瘤和恶性外周神经鞘瘤（MPNST）均起源于施万细胞谱系。尽管它们具有共同的起源，但这些肿瘤类型具有不同的病理学和临床行为；越来越多的证据表明，它们也通过不同的发病机制产生。鉴定出在以神经纤维瘤和 MPNST（神经纤维瘤病 1 [NF1]）或施万细胞瘤（神经纤维瘤病 2 [NF2]、施万细胞瘤病和卡尼综合征 1）发展为特征的遗传疾病中发生突变的基因，极大地促进了我们对这些机制的理解。通过基因工程小鼠消除 NF1、NF2、SMARCB1/INI1 或 PRKAR1A 的研究，证实了这些基因在外周神经鞘瘤发生中的关键作用。确定 NF1、NF2、SMARCB1/INI1 和 PRKAR1A 基因产物的功能，导致了促进施万细胞肿瘤发生的关键细胞质信号通路的鉴定，并确定了新的治疗靶点。对人类肿瘤和基因工程小鼠模型的分析表明，与其他肿瘤抑制因子如 TP53 和 CDKN2A 的相互作用促进了神经纤维瘤-MPNST 的进展，并表明肿瘤和非肿瘤细胞类型之间的肿瘤内相互作用在外周神经鞘瘤发生中起着至关重要的作用。最近的进展还为神经嵴衍生群体的身份提供了新的见解，这些群体产生不同类型的外周神经鞘瘤。基于这些发现，我们现在对外周神经鞘瘤的发病机制有了初步的分子机制概述。然而，这种认识的提高反过来又提出了一系列有趣的新问题。
