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Human Molecular Genetics Advance Access published online on July 11, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl165
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received March 24, 2006
Revised June 28, 2006
Accepted June 28, 2006

Article

Nf1+/- mast cells induce neurofibroma like phenotypes through secreted TGF-{beta} signaling

Feng-Chun Yang 1, Shi Chen 1, Travis Clegg 1, Xiaohong Li 1, Trent Morgan 1, Selina A. Estwick 1, Jin Yuan 1, Waleed Khalaf 2, Sarah Burgin 1, Jeff Travers 3, Luis F. Parada 4, David A. Ingram 5, and D. Wade Clapp 6 *

1 Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
2 Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA; Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
3 Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA; Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
4 Center for Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
5 Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
6 Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA; Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA; Indiana University School of Medicine, Cancer Research Institute, 1044 W. Walnut St., R4 402A, Indianapolis, IN 46202

* To whom correspondence should be addressed.
D. Wade Clapp, E-mail: dclapp{at}iupui.edu


  Abstract

Neurofibromas are common tumors found in neurofibromatosis type 1 patients (NF1). These complex tumors are composed of Schwann cells, mast cells, fibroblasts and perineurial cells embedded in collagen that provide a lattice for tumor invasion. Genetic studies demonstrate that in neurofibromas, nullizygous loss of Nf1 in Schwann cells and haploinsufficiency of Nf1 in non-neuronal cells is required for tumorigenesis. Fibroblasts are a major cellular constituent in neurofibromas and are a source of collagen that constitutes approximately 50% of the dry weight of the tumor. Here we show that two of the prevalent heterozygous cells found in neurofibromas, mast cells and fibroblasts, interact directly to contribute to tumor phenotype. Nf1+/- mast cells secrete elevated concentrations of the profibrotic growth factor TGF-{beta}?? In response to TGF-{beta}??both murine Nf1+/- fibroblasts and fibroblasts from human neurofibromas proliferate and synthesize excessive collagen, a hallmark of neurofibromas. We also establish that the TGF-{beta} response occurs via hyperactivation of a novel Ras-c-abl signaling pathway. Genetic or pharmacologic inhibition of c-abl reverses fibroblast proliferation and collagen synthesis to wildtype levels. These studies identify a novel molecular target to inhibit neurofibroma formation.


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