Pathogenesis of Plexiform Neurofibroma: Tumor-Stromal/Hematopoietic Interactions in Tumor Progression

Abstract

Neurofibromatosis type 1 (NF1) is a genetic disease that results from either heritable or spontaneous autosomal dominant mutations in the NF1 gene. A second-hit mutation precedes the predominant NF1 neoplasms, including myeloid leukemia, optic glioma, and plexiform neurofibroma formation. Despite this requisite NF1 loss of heterozygosity in the tumor cell of origin, non-tumorigenic cells contribute to both generalized and specific disease manifestations. In mouse models of plexiform neurofibroma formation, Nf1 haploinsufficient mast cells promote inflammation accelerating tumor formation and growth. These recruited mast cells, hematopoietic effector cells long known to permeate neurofibroma tissue, mediate key mitogenic signals promoting vascular in-growth, collagen deposition, and tumor growth. Thus, the plexiform neurofibroma microenvironment involves a tumor/stromal interaction with the hematopoietic system which depends, at the molecular level, on a stem cell factor/c-kit-mediated signaling axis. These observations parallel findings in other NF1 disease manifestations and have clear relevance toward medical neurofibroma management.