Neurofibromatosis type 1 (NF1) is an inherited disease characterized by the appearance of multiple neurofibromas and an increased incidence of malignant schwannomas, both of which contain hyperproliferative Schwann cells. Our laboratory previously reported that Schwann cells produce stem cell factor (SCF), a multi potential growth factor known to be involved in mast cell migration and growth. Given the fact that mast cell numbers are increased in both neurofibromas and malignant schwannomas, we set out to evaluate a potential role for SCF in the development of NF1 lesions. First we studied the effects of high doses of recombinant SCF on mast cell numbers in vivo, and found that dermal and peritoneal mast cell numbers were decreased. Next, we examined the expression of stem cell factor and its receptor, Kit, in neurofibromas and malignant schwannoma tumors and cell lines.
Using an RNase protection assay, we find that each of four human malignant schwannoma cell lines express only the membrane-bound isoform of SCF messenger RNA. In contrast, neurofibroma, vestibular schwannoma, and acoustic neuroma tissues, as well as the majority of human fibroblast sources, all express the soluble form. Low level expression of Kit protein was detected on all four malignant schwannoma cell lines. However, Kit expression by Schwann cells was not indicated by immunohistochemical analyses of neurofibroma and malignant schwannoma sections, although Kit was readily detected on the mast cells within these lesions. We report that bone marrow-derived mouse mast cells appear to be driven toward a connective tissue phenotype when cultured in the presence of conditioned media from Schwann cells of wild type and NF1 +/- knockout mice. This effect was not observed in cultures containing conditioned medium from Schwann cells of NF1 +/- knockouts. In addition, the latter appeared to augment the proliferation of mast cells in response to exogenous cytokines.
Together, these results suggest a significant role for stem cell factor and Kit in the lesions of NF1. In addition, functional neurofibromin, the product of the NF1 gene, may be required for proper regulation of SCF isoform expression. The mechanisms by which this expression is regulated remain to be clearly defined.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-6030 |
| Date | 01 January 1997 |
| Creators | Roth, Kenneth Eugene |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © The Author |
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