title: Neurofibromatosis type 1: Fundamental insights into cell signalling and cancer.
abstract: Neurofibromatosis type 1 (NF1) is an autosomal dominant tumour predisposition syndrome that is caused through loss of function mutations of a tumour suppressor gene called Neurofibromin 1. Therapeutic options are currently limited for NF1-associated tumours, where treatment is often restricted to complete surgical resection with clear margins. Herein, we discuss the multifunctional tumour suppressive role of neurofibromin, which is classically known as a GTPase activating protein (GAP) towards the RAS small GTPase. While neurofibromin inhibits proliferative growth through blockade of RAS-mediated signal transduction, neurofibromin should also be considered as a modulator of cell motility and cell adhesion. Through interfacing with the cytoskeleton and membrane structures, neurofibromin acts as a negative regulator of RHO/ROCK signalling pathways involved in cytoskeletal dynamics that are instrumental in proper neuronal development. In the context of cancer, the loss of normal function of neurofibromin via genetic mutation results in heightened cell proliferation and migration, predisposing NF1 patients to cancer. Malignant Peripheral Nerve Sheath Tumours (MPNSTs) can develop from benign neurofibromas and are the main cause of death amongst NF1 patients. Through recent research on MPNSTs, we have gained insight into the key molecular events that drive their malignancy. Advances regarding malignant drivers involved in cell migration, cell invasion and angiogenic signalling are discussed in this review, where these findings will likely influence future therapies for both NF1 and related sporadic cancers.
authors: Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors: Ellie
authors: E
authors: Rad
authors: Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. Electronic address: teea@cardiff.ac.uk.
authors: Andrew R
authors: AR
authors: Tee
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D018450:Disease Progression; D016147:Genes, Tumor Suppressor; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009456:Neurofibromatosis 1 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction
keywords: Cancer; MPNST; NF1; Neurofibromin; Tumour suppressor