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 c-kit 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 factor-dependent 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.

Figure 1

Examples of cutaneous and plexiform neurofibromas. Cutaneous neurofibromas growing on the chest and abdomen and an magnetic resonance image of a large plexiform neurofibroma compressing the spinal column. Photographs courtesy of the Children's Tumor Foundation; www.ctf.org.

Figure 2

Effect of haploinsufficiency of Nf1 on coat color and total numbers of cutaneous and peritoneal mast cells. (A) Coat color pattern of a representative mouse from each of the following genotypes: +/+;+/+, Nf1^+/−;+/+, +/+;W⁴¹/W⁴¹, and Nf1^+/−;W⁴¹/W⁴¹. Haploinsufficiency at Nf1 partially corrects the coat color deficiency in mice homozygous for the W41 allele in a C57BL/6 genetic background. (B) Representative cytospins from peritoneal lavages stained for mast cells from individual mice of the 4 Nf1 and W genotypes. Peritoneal cells were stained with toluidine blue to quantify the total number of mast cells per peritoneal lavage. A WT mouse (original magnification ×200). Bar (inset), 10 μm. Bar (far right), 30 μm. (C) Representative ear biopsies stained for cutaneous mast cells from individual mice of the 4 Nf1 and W genotypes. Specimens were stained with hematoxylin-eosin to assess routine histology and with Giemsa to identify mast cells. Ear biopsies were stained with Fontana-Masson to differentiate melanin-containing cells from mast cells. Cutaneous mast cells (Giemsa-positive, Fontana-Masson–negative) were quantitated in a blinded fashion by counting the distal 5 mm of ears. Black arrows indicate Giemsa-positive mast cells, and open arrows indicate Fontana-Masson melanin–containing cells. Bar, 35 μm. Originally published in Ingram et al.

Figure 3

Schematic of SCF:c-kit signaling in the mast cell. On SCF binding at the c-kit receptor tyrosine kinase (RTK), c-kit dimerizes and autophosphorylates. This phosphorylation promotes the conversion of Ras–guanine diphosphate (GDP) to Ras-GTP, which activates PI3K, MAPK, and Rho GTPase signaling pathways. NF1 potentiates the hydrolysis of Ras-GTP to Ras-GDP, the inactive form of Ras.

Figure 4

Potential cellular interactions in the plexiform neurofibroma microenvironment. NGF indicates nerve growth factor; and MMP, matrix metalloproteinase.

Figure 5

Transplantation schematic.

Figure 6

Evaluation of imatinib mesylate efficacy in an index patient with a plexiform neurofibroma. Coronal magnetic resonance imaging scans (T1-weighted images with gadolinium contrast and fat saturation) of the head and oropharynx of a patient with NF1 patient with a plexiform neurofibroma before (A) and 3 months after (B) treatment with imatinib mesylate. The region of the tumor in the respective images is indicated. Reprinted from Yang et al with permission from Elsevier.