Role of mast cells in the neurofibromatosis type 1-associated neurofibroma

Neurofibromatosis type 1 (NF1) afflicts about 1 in 3,000 persons and is the most common genetic disorder with a predisposition to malignancy. NF1 results from autosomal dominant mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. Neurofibromas, the hallmark tumor of NF1, are heterogeneous masses composed of Schwann cells, fibroblasts, perineural cells, mast cells, collagen, and blood vessels. Although mast cells were first observed in neurofibroma tissue nearly one hundred years ago, the hypothesis that mast cells play a critical role in the initiation and maintenance of NF1-associated tumors was not proposed until 1981. With continued research, mast cells, in concert with neurofibromin deficient Schwann cells, have emerged as primary pathogenic effectors in the neurofibroma tumor microenvironment. Moreover, recent marrow transplantation experiments have demonstrated that genetically aberrant mast cells are required for plexiform neurofibroma formation in a mouse tumor model. Utilizing the insights garnered from these transplantation studies and from other studies of heterotypic interactions between genetically altered Schwann cells, mast cells, and fibroblasts, clinicians are now trialing a medical therapy that may reduce or eliminate NF1-associated neurofibromas.