Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that occurs in about 1 out of 6000 live births. Patients with TSC suffer pain, disability, and death from tumors in multiple organs. Skin tumors are frequent, numerous, permanent, and disfiguring. Our long-term goal is to determine the molecular and genetic bases for these tumors. Tumor susceptibility is inherited as a mutation in the TSC2 tumor suppressor gene (or less commonly, the TSC1 gene). Tumors may form as a result of a second mutation eliminating the normal TSC2 allele. Using interphase fluorescence in situ hybridization (I-FISH), we have demonstrated that TSC skin tumors contain a genetically altered neoplastic cell population, marked by allelic deletion of TSC2. These """"""""two-hit"""""""" neoplastic cells make up a minority of the cells. This suggests that a major mechanism of TSC tumorigenesis is not rapid proliferation of neoplastic cells, but instead that neoplastic cells induce proliferation of surrounding cells. We hypothesize that TSC neoplastic cells induce proliferation of endothelial cells and fibroblasts by release of soluble factors, and that the surrounding fibroblasts, heterozygous for TSC2, likewise support the growth of the neoplastic cells.
The specific aims are: 1) to identify the location and morphology of neoplastic cells in TSC skin tumors by loss of heterozygosity studies on laser microdissected material, 2) to identify soluble factors over-expressed in TSC skin tumors using gene chip arrays combined with protein quantitation, and 3) to determine the effects of soluble factors on TSC tumorigenesis using in vitro assays. These studies focus on the cell-cell interactions that are clearly pertinent for the growth of TSC tumors and that result in the increased blood vessels and collagen formation. The elucidation of growth factors involved in these processes will provide molecular targets for the design of new therapies. ? ?
|Li, Shaowei; Thangapazham, Rajesh L; Wang, Ji-An et al. (2011) Human TSC2-null fibroblast-like cells induce hair follicle neogenesis and hamartoma morphogenesis. Nat Commun 2:235|
|Ikeda, Yoshihiko; Taveira-DaSilva, Angelo M; Pacheco-Rodriguez, Gustavo et al. (2011) Erythropoietin-driven proliferation of cells with mutations in the tumor suppressor gene TSC2. Am J Physiol Lung Cell Mol Physiol 300:L64-72|
|Seibert, Diane; Hong, Chien-Hui; Takeuchi, Fumiko et al. (2011) Recognition of tuberous sclerosis in adult women: delayed presentation with life-threatening consequences. Ann Intern Med 154:806-13, W-294|
|Cai, Xiong; Pacheco-Rodriguez, Gustavo; Fan, Qing-Yuan et al. (2010) Phenotypic characterization of disseminated cells with TSC2 loss of heterozygosity in patients with lymphangioleiomyomatosis. Am J Respir Crit Care Med 182:1410-8|
|Aldrich, Capt Shelley L; Hong, Chien-Hui; Groves, Leslie et al. (2010) Acral lesions in tuberous sclerosis complex: insights into pathogenesis. J Am Acad Dermatol 63:244-51|
|Li, Shaowei; Takeuchi, Fumiko; Wang, Ji-An et al. (2008) Mesenchymal-epithelial interactions involving epiregulin in tuberous sclerosis complex hamartomas. Proc Natl Acad Sci U S A 105:3539-44|
|Sparling, Joshua D; Hong, Chien-Hui; Brahim, Jaime S et al. (2007) Oral findings in 58 adults with tuberous sclerosis complex. J Am Acad Dermatol 56:786-90|
|Pacheco-Rodriguez, Gustavo; Steagall, Wendy K; Crooks, Denise M et al. (2007) TSC2 loss in lymphangioleiomyomatosis cells correlated with expression of CD44v6, a molecular determinant of metastasis. Cancer Res 67:10573-81|
|Li, Shaowei; Takeuchi, Fumiko; Wang, Ji-an et al. (2005) MCP-1 overexpressed in tuberous sclerosis lesions acts as a paracrine factor for tumor development. J Exp Med 202:617-24|