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 3

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Quantification of the concentration of KitL in Schwann cell CM and the e...
Quantification of the concentration of KitL in Schwann cell CM and the effect of pharmacologic or genetic inhibition of c-kit activity on mast cell migration to Schwann cell CM. (a) Concentration of murine KitL in WT, Nf1+/–, and Nf1–/– Schwann cell CM was determined by ELISA. Results represent the mean ± SEM of five independent collections from five independent Schwann cell cultures. *P < 0.05 for Nf1–/– versus WT or Nf1–/– versus Nf1+/– by the Student’s paired t test. (b) WT and Nf1+/– mast cells (2 × 105) were preincubated with a neutralizing Ab to the c-kit RTK, and haptotaxis assays were performed to either WT or Nf1–/– Schwann cell CM. Results represent the mean ± SEM of five independent experiments. *P < 0.05 for WT mast cell migration in response to WT or Nf1–/– Schwann cell CM in the presence or absence of the c-kit–neutralizing Ab. **P < 0.05 for Nf1+/– mast cell migration in response to WT or Nf1–/– Schwann cell CM in the presence or absence of the c-kit–neutralizing Ab by the Student’s paired t test. (c) Haptotaxis of mast cells of the four Nf1 and W genotypes in response to either 2 × 105 WT or Nf1–/– Schwann cell CM. Results represent the mean ± SEM of five independent experiments. *P < 0.05 for W41/W41 versus WT mast cell migration in response to either WT or Nf1–/– Schwann cell CM. **P < 0.05 for Nf1+/–; W41/W41 versus Nf1+/– mast cell migration in response to either WT or Nf1–/– Schwann cell CM by the Student’s paired t test.