Background: 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.
Methods: 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.
Results and conclusions: 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.