Neurofibromatosis type 1 peripheral nerve tumors: Aberrant activation of the Ras pathway

BACKGROUND Neurofibromatosis Type 1 (NF1) is an autosomal dominant transmitted cancer predisposing syndrome, with peripheral nerve tumors being a prominent featu re. 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 sa rcoma cell lines, that loss of neurofibromin leads to increased levels of a ctivated Ras-GTP, and subsequent uncontrolled mitogenic signals to the nucl eus. However, it is not known whether aberrant activity of the Ras pathway is also a prevalent molecular pathogenetic mechanism in actual peripheral n erve tumors. METHODS To investigate whether aberrant Ras activity was present, and varied with i ncreased tumorigenic potential in peripheral nerve tumors, we have recently developed and published an enzymatic luciferase-based assay that allows me asurement 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 N F1 tumors. Levels of activated Ras-GTP in NF1 neurogenic sarcomas and NF1 p lexiform neurofibromas were approximately 15 and 5 times higher, respective ly, compared with non-NF1 schwannomas, supporting the hypothesis that aberr ant activity of this key signaling pathway is important in the pathogenesis of these tumors. In this article we review this data, the molecular geneti cs of NF1, and the current knowledge of the role of neurofibromin in cellul ar control. Our understanding of the molecular pathogenic mechanisms of NF1 tumors should be transferable to sporadic peripheral nerve tumors, and all ow development of biological therapies directed against relevant targets su ch as Ras, (C) 1999 by Elsevier Science Inc.