Molecular mechanisms promoting the pathogenesis of Schwann cell neoplasms.
Molecular mechanisms promoting the pathogenesis of Schwann cell neoplasms.
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DOI：
10.1007/s00401-011-0928-6
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发表时间：
2012-03
影响因子：
12.7
通讯作者：
Carroll SL
中科院分区：
文献类型：
--
作者：
Carroll SL
神经纤维瘤、神经鞘瘤和恶性外周神经鞘瘤（MPNSTs）都起源于雪旺细胞谱系。尽管它们有共同的起源，但这些肿瘤类型具有不同的病理和临床行为;越来越多的证据表明它们也是通过不同的致病机制产生的。在以神经纤维瘤和MPNST [1型神经纤维瘤病（NF1）]或神经鞘瘤[2型神经纤维瘤病（NF2），神经鞘瘤病和Carney复合体1型]发展为特征的遗传性疾病中突变基因的鉴定大大促进了我们对这些机制的理解。通过消融NF 1、NF 2、SMARCB 1/INI1或PRKAR 1A的基因工程小鼠的发展证实了这些基因在外周神经鞘肿瘤发生中发挥的关键作用。确定NF 1、NF 2、SMARCB 1/INI1和PRKAR 1A基因产物的功能，导致鉴定了促进雪旺细胞瘤形成的关键细胞质信号传导途径，并鉴定了新的治疗靶点。对人类肿瘤和基因工程小鼠模型的分析已经确定，与其他肿瘤抑制因子如TP53和CDKN2A的相互作用促进神经纤维瘤-MPNST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肿瘤发生中起重要作用。最近的进展也提供了新的见解的身份神经嵴衍生的人口，引起不同类型的周围神经鞘肿瘤。基于这些发现，我们现在对神经纤维瘤、MPNST和神经鞘瘤的发病机制有了初步的认识。然而，这种理解的提高反过来又提出了一系列有趣的新问题。
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.
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