Neurofibromatosis Type 1 (NF1) is a common autosomal dominant disease characterized by complex and multicellular
neurofibroma tumors, and less frequently by
malignant peripheral nerve sheath tumors (MPNSTs) and
optic nerve gliomas. Significant advances have been made in elucidating the cellular, genetic, and molecular biology involved in
tumor formation in NF1.
Neurofibromatosis Type 1 is caused by germline mutations of the NF1 tumor suppressor gene, which generally result in decreased intracellular
neurofibromin protein levels, leading to increased cascade Ras signaling to its downstream effectors. Multiple key pathways are involved with the development of
tumors in NF1, including Ras/
mitogen-activated protein kinase (MAPK) and Akt/
mammalian target of rapamycin (mTOR). Interestingly, recent studies demonstrate that multiple other developmental syndromes (in addition to NF1) share phenotypic features resulting from germline mutations in genes responsible for components of the Ras/MAPK pathway. In general, a somatic loss of the second NF1 allele, also referred to as loss of heterozygosity, in the progenitor cell, either the Schwann cell or its precursor, combined with haploinsufficiency in multiple supporting cells is required for
tumor formation. Importantly, a complex series of interactions with these other cell types in
neurofibroma tumorigenesis is mediated by abnormal expression of
growth factors and their receptors and modification of gene expression, a key example of which is the process of recruitment and involvement of the NF1(+/-) heterozygous mast cell. In general, for malignant transformation to occur, there must be accumulation of additional mutations of multiple genes including INK4A/ARF and P53, with resulting abnormalities of their respective signal cascades. Further, abnormalities of the NF1 gene and molecular cascade described above have been implicated in the
tumorigenesis of NF1 and some sporadically occurring
gliomas, and thus, these treatment options may have wider applicability. Finally, increased knowledge of molecular and cellular mechanisms involved with NF1
tumorigenesis has led to multiple preclinical and clinical studies of targeted
therapy, including the mTOR inhibitor
rapamycin, which is demonstrating promising preclinical results for treatment of MPNSTs and
gliomas.