Genetically engineered mouse models shed new light on the pathogenesis of neurofibromatosis type I-related neoplasms of the peripheral nervous system.
Genetically engineered mouse models shed new light on the pathogenesis of neurofibromatosis type I-related neoplasms of the peripheral nervous system.
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DOI：
10.1016/j.brainresbull.2011.08.005
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发表时间：
2012-05-01
影响因子：
3.8
通讯作者：
Carroll SL
中科院分区：
文献类型：
--
作者：
Brossier NM;Carroll SL
1型神经纤维瘤病（NF 1）是影响人类神经系统的最常见的遗传性疾病，其特征在于皮肤和大的周围神经中多发性良性雪旺细胞瘤的发展。这些肿瘤，分别被称为皮肤和丛状神经纤维瘤，有不同的临床过程，特别注意，丛状，但不是皮肤，神经纤维瘤往往经历恶性进展，形成恶性外周神经鞘瘤（MPNST），最常见的恶性肿瘤发生在NF 1患者。近年来，已经建立了许多基因工程小鼠模型来研究驱动这些肿瘤发病机制的分子机制。这些模型被设计用于解决关键问题，包括：1）雪旺细胞谱系中的NF 1丢失是否是肿瘤发生所必需的; 2）雪旺细胞谱系中的什么细胞类型引起真皮神经纤维瘤、丛状神经纤维瘤和MPNST; 3）肿瘤微环境如何促成瘤形成; 4）什么额外的突变促成神经纤维瘤-MPNST进展; 5）不同的神经纤维蛋白调节的Ras蛋白在此过程中起什么作用以及6）失调的生长因子信号传导如何促进PNS肿瘤发生。在这篇综述中，我们总结了这些模型的主要研究结果及其局限性，以及如何协调这些模型之间的差异。我们还讨论了如何从这些模型中收集的信息可以合成到一个全面的模型，周围神经系统的肿瘤形成，并考虑几个主要的问题，仍然没有回答这个过程。
Neurofibromatosis type 1 (NF1), the most common genetic disorder affecting the human nervous system, is characterized by the development of multiple benign Schwann cell tumors in skin and large peripheral nerves. These neoplasms, which are termed dermal and plexiform neurofibromas respectively, have distinct clinical courses; of particular note, plexiform, but not dermal, neurofibromas often undergo malignant progression to form malignant peripheral nerve sheath tumors (MPNSTs), the most common malignancy occurring in NF1 patients. In recent years, a number of genetically engineered mouse models have been created to investigate the molecular mechanisms driving the pathogenesis of these tumors. These models have been designed to address key questions including: 1) whether NF1 loss in the Schwann cell lineage is essential for tumorigenesis; 2) what cell type(s) in the Schwann cell lineage gives rise to dermal neurofibromas, plexiform neurofibromas and MPNSTs; 3) how the tumor microenvironment contributes to neoplasia; 4) what additional mutations contribute to neurofibroma-MPNST progression; 5) what role different neurofibromin-regulated Ras proteins play in this process and 6) how dysregulated growth factor signaling facilitates PNS tumorigenesis. In this review, we summarize the major findings from each of these models and their limitations as well as how discrepancies between these models may be reconciled. We also discuss how information gleaned from these models can be synthesized to into a comprehensive model of tumor formation in peripheral nervous system and consider several of the major questions that remain unanswered about this process.
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影响因子：
30.8
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