Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/– mast cells
Yang Feng-Chun, … , Simon J. Atkinson, D. Wade Clapp
Yang Feng-Chun, … , Simon J. Atkinson, D. Wade Clapp
Published December 15, 2003
Citation Information: J Clin Invest. 2003;112(12):1851-1861. https://doi.org/10.1172/JCI19195.
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Article Oncology

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 IA-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.

Authors

Yang Feng-Chun, David A. Ingram, Shi Chen, Cynthia M. Hingtgen, Nancy Ratner, Kelly R. Monk, Travis Clegg, Hilary White, Laura Mead, Mary Jo Wenning, David A. Williams, Reuben Kapur, Simon J. Atkinson, D. Wade Clapp

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Figure 2

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Effect of WT, Nf1+/–, and Nf1–/– Schwann cell CM on WT and Nf1+/– mast c...
Effect of WT, Nf1+/–, and Nf1–/– Schwann cell CM on WT and Nf1+/– mast cell haptotaxis. (a) Transwells were coated with recombinant FN and mast cell migration assays were performed in response to WT, Nf1+/–, and Nf1–/– Schwann cell CM. The number of WT and Nf1+/– mast cells that had migrated to the bottom surface of the FN-coated membrane in response to Schwann cell CM were counted after staining the cells with crystal violet. A representative photomicrograph of the WT- and Nf1+/–-migrated mast cells, which stain purple, is shown for each experimental condition. (b) The average numbers of WT and Nf1+/– mast cells per ten high-power fields, which migrated in response to either 105 WT, Nf1+/–, or Nf1–/– Schwann cell CM are shown. Data represent the mean number of migrated cells per ten high-power fields ± SEM of four independent experiments. *P < 0.05 for Nf1+/– versus WT mast cells in response to either WT Schwann cell CM or Nf1+/– Schwann cell CM. **P < 0.05 for WT mast cells in response to both WT and Nf1+/– Schwann cell CM versus Nf1–/– Schwann cell CM; ***P < 0.01 for Nf1+/– mast cells in response to both WT and Nf1+/– versus Nf1–/– Schwann cell CM by the Student’s paired t test. HPF, high-power field.