Mast cells and the neurofibroma microenvironment

Abstract

Neurofibromatosis type 1 (NF1) is the most common genetic disorder with a predisposition to malignancy and affects 1 in 3500 persons worldwide. NF1 is caused by a mutation in the NF1 tumor suppressor gene that encodes the protein neurofibromin. Patients with NF1 have cutaneous, diffuse, and plexiform neurofibromas, tumors comprised primarily of Schwann cells, blood vessels, fibroblasts, and mast cells. Studies from human and murine models that closely recapitulate human plexiform neurofibroma formation indicate that tumorigenesis necessitates NF1 loss of heterozygosity in the Schwann cell. In addition, our most recent studies with bone marrow transplantation and pharmacologic experiments implicate haploinsufficiency of Nf1 (Nf1 ؉/؊ ) and ckit signaling in the hematopoietic system as required and sufficient for tumor progression. Here, we review recent studies implicating the hematopoietic system in plexiform neurofibroma genesis, delineate the physiology of stem cell factordependent hematopoietic cells and their contribution to the neurofibroma microenvironment, and highlight the application of this research toward the first successful, targeted medical treatment of a patient with a nonresectable and debilitating neurofibroma. Finally, we emphasize the importance of the tumor microenvironment hypothesis, asserting that tumorigenic cells in the neurofibroma do not arise and grow in isolation. (Blood. 2010; 116(2):157-164) IntroductionAlthough several reports characterized neurofibromatosis type 1 (NF1) or NF1-like syndromes as early as the 18th century, [1][2][3] Friedrich von Recklinghausen did not publish his seminal, detailed case reports until 1882. 4 Von Recklinghausen observed that neurofibromas contain elements of both neuronal and fibroblastic tissue. In 1911, H. Greggio reported his observation that mast cells infiltrate the neurofibroma. 5,6 Vincent Riccardi later postulated a pivotal role for mast cells and melanocytes in NF1 pruritus, pigmentation defects, and, potentially, neurofibroma formation. 7 Today, NF1 is recognized as a common and fully penetrant genetic disease that shows variable expressivity. 6-9 The disease is transmitted in an autosomal dominant fashion as a mutation in NF1, a tumor suppressor gene encoding the protein neurofibromin. Neurofibromin functions as a p21 ras (Ras) guanosine triphosphatase (GTP)-activating protein (GAP), accelerating the hydrolysis of Ras-GTP thousands of fold and functioning at least in part to negatively regulate multiple Ras-dependent cellular signaling pathways. 6,[10][11][12][13][14][15][16] Mutations of NF1 predispose patients to variable neuronal, hematopoietic, and skeletal disorders, including myeloid leukemia, kyphoscoliosis, long bone pseudoarthrosis, and cutaneous, subcutaneous, and diffuse plexiform neurofibromas. 6,17 Neurofibromas are pathognomonic for the disease. Cutaneous neurofibromas arise from small peripheral nerves during adolescence or adulthood and are observed in greater than 95% of patients with NF1 (Figure 1 left). 18 Plexiform neu...

Molecular and Clinical Aspects of Drug-induced Gingival Overgrowth

“…It is currently unclear whether there is a corresponding phenotypic switch from inflammatory M1 macrophages to synthetic M2 macrophages in NF1. Interactions between inflammatory cells and connective tissue cells leading to proliferative and fibrotic consequences are likely, but still only partially understood (Staser et al 2010;Prada et al 2013). Increased release of TGF-β in particular from mast cells and/or macrophages is suspected as being a driving force in the development of both gingival overgrowth and neurofibromas (Saito et al 1996;Tipton and Dabbous 1998;Ling et al 2005;Yang et al 2006).…”

Expression of S-100, EMA, CD34 and presence of mast cells in eight oral neurofibromas, and a review of 127 cases of the literature

“…Mast cells can also be identified by other histochemical techniques: for example, by the use of dyes such as toluidine blue solution (31) , and by immunohistochemistry using tryptase (27) , CD 117 (c-kit) or calretinin (11) as markers. Few studies have identified mast cells in neurofibromas by immunohistochemical and histochemical methods, despite the important role attributed to these cells in the pathogenesis of this lesion (14,33,35) . The identification of mast cells, even in small numbers, can aid in the diagnosis of this neoplasm, particularly if the identification is associated with other immunomarkers of neurofibromas.…”

“…The consequent mast cell migration causes the secretion of the growth factors and cytokines necessary for the initiation and progression of the tumor, as well as the factors necessary for neoangiogenesis, including nerve growth factor (NGF), vascular endothelial growth factor (VEGF), fibroblast growth factor, transforming growth factor beta (TGF-β), and others. Fibroblasts, Schwann cells, perineural-like cells and endothelial cells with a mutation in one of the NF1 alleles (Nf1 +/-) seem to be responsive to the neoplastic environment (14,33,35) .…”

“…This gene encodes the protein neurofibromin, which inactivates the RAS intracellular signaling cascade, a key component of many growth factor signaling pathways. In the absence of neurofibromin, the RAS cascade is constitutively activated, resulting in increased cellular proliferation and survival (14,33,35) .…”

A Case of Solitary Neurofibroma in Outer Surface of Nose

“…This tumor essentially is composed of Schwann cells arising from a peripheral nerve and usually affects skin or subcutaneous tissue. 3,4 Neurofibroma is generally presented in background of Von Recklinghausen's disease, but it can also appear solitarily. 5 This tumor is usually found in the head and neck and the flexor surfaces of the extremities.…”