transforming-growth-factor-beta and Neurofibroma

Neurofibromas in von Recklinghausen's disease (vRD) can develop in the dermis. Therefore, we hypothesized that a dermal niche exists that promotes the development of these neurofibromas in subjects with vRD.. The purpose of this study is to examine the function of polydom, known as a ligand for integrin, mediating cell adhesion, and expressed in mouse nerve tissue, in promotion of neurofibroma.. Molecular, transcriptome and immunohistochemical analysis were performed to investigate the association between polydom expression and neurofibroma development.. Polydom mRNA levels were significantly higher in neurofibroma tissue than in control tissue. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis of RNA purified from primary cultured dermal neurofibroma cells demonstrated significantly higher polydom mRNA expression in cells derived from the surrounding dermis of neurofibromas compared to those from normal human dermal fibroblasts. RNA sequencing was used to compare gene expression between cultured cells derived from dermal neurofibroma-surrounding tissue with or without polydom knockdown. Subsequent gene ontology assays revealed that expression of integrinβ8 (ITGB8), a factor that releases transforming growth factor-β (TGF-β) from pro-TGF-β, was downregulated following polydom knockdown, suggesting upregulation of polydom-mediated TGF-β production. Furthermore, we observed a strong association between polydom expression and the increase in platelet-derived growth factor B (PDGFB) expression in primary cultured cells from the surrounding dermis of neurofibromas exposed to TGF-β1.. Our results suggest that increased polydom expression in the dermis surrounding neurofibromas may promote dermal neurofibroma development by activating the TGF-β signaling pathway.

Topics: Adolescent; Adult; Aged; Base Sequence; Cell Adhesion; Cell Adhesion Molecules; Dermis; Female; Fibroblasts; Gene Expression Regulation; Humans; Integrin beta Chains; Male; Middle Aged; Neurofibroma; Neurofibromatosis 1; Proto-Oncogene Proteins c-sis; RNA, Small Interfering; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factor beta1; Young Adult

Topics: Humans; Neurofibroma; Neurofibromatosis 1; Taurine; Transforming Growth Factor beta

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.

Topics: Animals; Benzamides; Bone Marrow Cells; Cell Movement; Cell Proliferation; Collagen; Culture Media, Conditioned; Embryo, Mammalian; Fibroblasts; Fibrosis; Haplotypes; Heterozygote; Humans; Imatinib Mesylate; Mast Cells; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Neurofibroma; Neurofibromatosis 1; Phenotype; Piperazines; Proto-Oncogene Proteins c-abl; Proto-Oncogene Proteins p21(ras); Pyrimidines; Signal Transduction; Transforming Growth Factor beta

In neurofibromatosis type-1 (NF-1), abnormal growth regulation may be related to the formation of multiple neurofibromas. We investigated the growth responses of neurofibroma-derived cells (NF cells) and control skin fibroblasts to various growth factors. The responses to platelet-derived growth factor (PDGF-BB) and transforming growth factor-beta 1 (TGF-beta 1) in NF cells were significantly greater than those in control fibroblasts. The increased response to PDGF-BB in NF cells was accompanied by an increased number of PDGF beta receptors, which was demonstrated by both 125I PDGF-BB binding assay and immunoblotting analysis. The increased response to TGF-beta 1 was assumed to be mediated through PDGF-like protein induction; TGF-beta 1-treated NF cells produced greater amounts of 36-kD PDGF-like protein than TGF-beta 1-treated control fibroblasts. These observations suggest that certain growth factors, e.g., PDGF-BB and TGF-beta, may play some role in the development of neurofibromas in NF-1.

Topics: Becaplermin; Cell Division; Cells, Cultured; Fibroblasts; Humans; Immunoblotting; Kinetics; Neurofibroma; Neurofibromatosis 1; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Receptors, Platelet-Derived Growth Factor; Recombinant Proteins; Skin; Skin Neoplasms; Thymidine; Transforming Growth Factor beta; Tumor Cells, Cultured