Nf1-/- Schwann cell-conditioned medium modulates mast cell degranulation by c-Kit-mediated hyperactivation of phosphatidylinositol 3-kinase

Shi Chen, Sarah Burgin, Andrew McDaniel, Xiaohong Li, Jin Yuan, Mia Chen, Waleed Khalaf, D. Wade Clapp, Feng Chun Yang

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Neurofibromatosis type 1 (NF1) is a common genetic disorder and is characterized by both malignant and nonmalignant neurofibromas, which are composed of Schwann cells, degranulating mast cells, fibroblasts, and extracellular matrix. We and others have previously shown that hyperactivation of the c-Kit pathway in an Nf1 haploinsufficient microenvironment is required for both tumor formation and progression. Mast cells play a key role in both tumorigenesis and neoangiogenesis via the production of matrix metalloproteinases, heparin, and a range of different growth factors. In the present study, we show that tumorigenic Schwann cells derived from Nf1 -/- embryos promote increased degranulation of Nf1+/- mast cells compared with wild-type mast cells via the secretion of the Kit ligand. Furthermore, we used genetic intercrosses as well as pharmacological agents to link the hyperactivation of the p21Ras-phosphatidylinositol 3-kinase (PI3K) pathway to the increased degranulation of Nf1+/- mast cells both in vitro and in vivo. These studies identify the p21Ras-PI3K pathway as a major regulator of the gain in Nf1+/- mast cell degranulation in neurofibromas. Collectively, these studies identify both c-Kit and PI3K as molecular targets that modulate mast cell functions in cases of NF1.

Original languageEnglish (US)
Pages (from-to)3125-3132
Number of pages8
JournalAmerican Journal of Pathology
Volume177
Issue number6
DOIs
StatePublished - Dec 2010

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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