Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/– mast cells

Abstract

The NF1 tumor suppressor gene encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras signaling. Mutations in NF1 cause neurofibromatosis type 1 (NF1). The development of neurofibromas, which are complex tumors composed of multiple cell types, is a hallmark of NF1. Somatic inactivation of murine Nf1 in Schwann cells is necessary, but not sufficient, to initiate neurofibroma formation. Neurofibromas occur with high penetrance in mice in which Nf1 is ablated in Schwann cells in the context of a heterozygous mutant (Nf1 +/-) microenvironment. Mast cells infiltrate neurofibromas, where they secrete proteins that can remodel the ECM and initiate angiogenesis. Thus, identification of mechanisms responsible for mast cell migration to tumor microenvironments is important for understanding tumorigenesis and for designing potential therapies. Here, we show that homozygous Nf1 mutant (Nf1 -/-) Schwann cells secrete Kit ligand (KitL), which stimulates mast cell migration, and that Nf1 +/-mast cells are hypermotile in response to KitL. Furthermore, we link hyperactivation of the Ras-class I A -PI3K-Rac2 pathway to increased Nf1 +/-mast cell migration. Thus, these studies identify a novel interaction between Nf1 -/-Schwann cells and Nf1 +/-mast cells that is likely to be important in neurofibroma formation.

It takes two to tango: mast cell and Schwann cell interactions in neurofibromas

“…Additional studies have since supported the finding of mast cells in peripheral nerve trunks (10,11), peripheral nerve tumors (12)(13)(14), and neurofibromas in neurofibromatosis 1 (15)(16)(17). The potential involvement of the c-Kit receptor and its ligand (18,19) in the formation of neurofibromas has also been reported, but Yang et al (2) are the first investigators to evaluate living cells of different genetic backgrounds in order to demonstrate how increased mast cells populate neurofibromas. Now that a plausible mechanism has been established for the migration of mast cells to developing neurofibromas, it is important to dissect potential mechanisms whereby mast cells can induce cells in the microenvironment to either tolerate or enhance cell proliferation.…”

“…He was attempting to explain the variable expression of neurofibromatosis 1 (NF1) by cellular interactions and the finding of high numbers of mast cells in neurofibromas when he posited that "the mast cell now is seen not as a secondary arrival in a developing neurofibroma but as an inciting factor contributing in a primary, direct fashion to tumor development." It has taken over 20 years, but in this issue of the JCI, Yang et al (2) clearly set the record straight by identifying the molecular mechanisms underlying mast cell infiltration of neurofibromas. The authors demonstrated that the inciting factor for mast cell migration is Kit ligand and that it is hypersecreted from Nf1 -/-Schwann cell populations.…”

“…He followed up this study with a controlled multiphase trial of ketotifen in 27 patients, assessing pain and itching associated with neurofibromas, and showed a response (24) that was reviewed as encouraging, but not definitely beneficial (25). Given that specific paracrine pathways have yet to be defined in the microenvironment of NF1-related neurofibromas, Yang et al (2) appropriately point out that therapeutic agents that target the migration of mast cells (i.e., inhibition of c-kit activity and adhesion to α4β1 integrin) may hold promise in the early treatment and/or prevention of neurofibromas.…”

“…This supports the paracrine model for neurofibromas; other cells in these mixed-cell tumors must be haploinsufficient for neurofibromin to support proliferation. Yang et al (2) have taken these observations a step further by dissecting the cell types and the molecular mechanisms by which the tumor microenvironment contributes to neurofibroma formation. Through a set of elegant experiments, they have delineated a complex biological system and provided a model demonstrating not just who the major players are in this process, but how those players interact in concert to develop neurofibromas (Figure 1).…”

Mammary tumor growth and metastasis are reduced in c‐Kit mutant Sash mice

“…They are primarily known for their role in allergic responses 1. However, in the last 15 years, studies mainly using mouse models for various types of cancers, including squamous carcinoma 2, neurofibromatosis 3, 4, and pancreatic islet tumor 5, reveal the tumor‐promoting role of mast cells in different cancers. Meanwhile, the suppressive function of mast cells in cancer was implicated in a few studies, including in intestinal tumorigenesis 6.…”