Nf1+/- mast cells induce neurofibroma like phenotypes through secreted TGF-beta signaling.
Neurofibromas are common tumors found in neurofibromatosis type 1 (NF1) patients. 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 are 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 transforming growth factor-beta (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 pharmacological inhibition of c-abl reverses fibroblast proliferation and collagen synthesis to wild-type levels. These studies identify a novel molecular target to inhibit neurofibroma formation.
Yang
Feng-Chun
FC
Department of Pediatrics, and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, 1044 W. Walnut Street, Indianapolis, IN 46202, USA.
Chen
Shi
S
Clegg
Travis
T
Li
Xiaohong
X
Morgan
Trent
T
Estwick
Selina A
SA
Yuan
Jin
J
Khalaf
Waleed
W
Burgin
Sarah
S
Travers
Jeff
J
Parada
Luis F
LF
Ingram
David A
DA
Clapp
D Wade
DW
D000818:Animals; D001549:Benzamides; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D003094:Collagen / Q000096:biosynthesis; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000209:etiology; D006239:Haplotypes / Q000502:physiology; D006579:Heterozygote; D006801:Humans; D000068877:Imatinib Mesylate; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009455:Neurofibroma / Q000209:etiology*; D009456:Neurofibromatosis 1 / Q000235:genetics*; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000502:physiology*
D001549:Benzamides; D017077:Culture Media, Conditioned; D010879:Piperazines; D011743:Pyrimidines; D016212:Transforming Growth Factor beta; D000068877:Imatinib Mesylate; D003094:Collagen; D016315:Proto-Oncogene Proteins c-abl; D016283:Proto-Oncogene Proteins p21(ras)