Feldkamp M M, Angelov L, Guha A
Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Surg Neurol. 1999 Feb;51(2):211-8. doi: 10.1016/s0090-3019(97)00356-x.
Neurofibromatosis Type 1 (NF1) is an autosomal dominant transmitted cancer predisposing syndrome, with peripheral nerve tumors being a prominent feature. The NF1 gene encodes a large cytoplasmic protein called neurofibromin, which is a major negative regulator of Ras, a key protein in a major signal transduction pathway. It is hypothesized, based on data from neurogenic sarcoma cell lines, that loss of neurofibromin leads to increased levels of activated Ras-GTP, and subsequent uncontrolled mitogenic signals to the nucleus. However, it is not known whether aberrant activity of the Ras pathway is also a prevalent molecular pathogenetic mechanism in actual peripheral nerve tumors.
To investigate whether aberrant Ras activity was present, and varied with increased tumorigenic potential in peripheral nerve tumors, we have recently developed and published an enzymatic luciferase-based assay that allows measurement of Ras activity in tissues for the first time.
Neurofibromin, the gene product of the NF1 gene, was not expressed in the NF1 tumors. Levels of activated Ras-GTP in NF1 neurogenic sarcomas and NF1 plexiform neurofibromas were approximately 15 and 5 times higher, respectively, compared with non-NF1 schwannomas, supporting the hypothesis that aberrant activity of this key signaling pathway is important in the pathogenesis of these tumors. In this article we review this data, the molecular genetics of NF1, and the current knowledge of the role of neurofibromin in cellular control. Our understanding of the molecular pathogenic mechanisms of NF1 tumors should be transferable to sporadic peripheral nerve tumors, and allow development of biological therapies directed against relevant targets such as Ras.
1型神经纤维瘤病（NF1）是一种常染色体显性遗传的癌症易感综合征，周围神经肿瘤是其突出特征。NF1基因编码一种名为神经纤维瘤蛋白的大型细胞质蛋白，它是Ras的主要负调节因子，Ras是主要信号转导通路中的关键蛋白。基于神经源性肉瘤细胞系的数据推测，神经纤维瘤蛋白的缺失会导致活化的Ras - GTP水平升高，进而向细胞核传递不受控制的促有丝分裂信号。然而，尚不清楚Ras通路的异常活性是否也是实际周围神经肿瘤中普遍存在的分子致病机制。
为了研究周围神经肿瘤中是否存在Ras异常活性，以及其是否随致瘤潜能增加而变化，我们最近开发并发表了一种基于酶促荧光素酶的检测方法，该方法首次能够测量组织中的Ras活性。
NF1基因的产物神经纤维瘤蛋白在NF1肿瘤中未表达。与非NF1神经鞘瘤相比，NF1神经源性肉瘤和NF1丛状神经纤维瘤中活化的Ras - GTP水平分别高出约15倍和5倍，这支持了这一关键信号通路的异常活性在这些肿瘤发病机制中起重要作用的假设。在本文中，我们回顾了这些数据、NF1的分子遗传学以及目前对神经纤维瘤蛋白在细胞控制中作用的认识。我们对NF1肿瘤分子致病机制的理解应可应用于散发性周围神经肿瘤，并有助于开发针对Ras等相关靶点的生物疗法。
