Abstract |
Patients with tuberous sclerosis complex ( TSC) develop hamartomatous tumors showing loss of function of the tumor suppressor TSC1 ( hamartin) or TSC2 ( tuberin) and increased angiogenesis, fibrosis, and abundant mononuclear phagocytes. To identify soluble factors with potential roles in TSC tumorigenesis, we screened TSC skin tumor-derived cells for altered gene and protein expression. Fibroblast-like cells from 10 angiofibromas and five periungual fibromas produced higher levels of monocyte chemoattractant protein-1 (MCP-1) mRNA and protein than did fibroblasts from the same patient's normal skin. Conditioned medium from angiofibroma cells stimulated chemotaxis of a human monocytic cell line to a greater extent than conditioned medium from TSC fibroblasts, an effect blocked by neutralizing MCP-1-specific antibody. Overexpression of MCP-1 seems to be caused by loss of tuberin function because Eker rat embryonic fibroblasts null for Tsc2 (EEF Tsc2(-/-)) produced 28 times as much MCP-1 protein as did EEF Tsc2(+/+) cells; transient expression of WT but not mutant human TSC2 by EEF Tsc2(-/-) cells inhibited MCP-1 production; and pharmacological inhibition of the Rheb-mTOR pathway, which is hyperactivated after loss of TSC2, decreased MCP-1 production by EEF Tsc2(-/-) cells. Together these findings suggest that MCP-1 is an important paracrine factor for TSC tumorigenesis and may be a new therapeutic target.
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Authors | Shaowei Li, Fumiko Takeuchi, Ji-an Wang, Christopher Fuller, Gustavo Pacheco-Rodriguez, Joel Moss, Thomas N Darling |
Journal | The Journal of experimental medicine
(J Exp Med)
Vol. 202
Issue 5
Pg. 617-24
(Sep 05 2005)
ISSN: 0022-1007 [Print] United States |
PMID | 16129702
(Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Antibodies
- CCL2 protein, human
- Chemokine CCL2
- Culture Media, Conditioned
- TSC2 protein, human
- Tsc2 protein, rat
- Tuberous Sclerosis Complex 2 Protein
- Tumor Suppressor Proteins
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Topics |
- Analysis of Variance
- Animals
- Antibodies
(metabolism)
- Chemokine CCL2
(metabolism)
- Chemotaxis
(drug effects)
- Culture Media, Conditioned
(pharmacology)
- Enzyme-Linked Immunosorbent Assay
- Fibroblasts
(metabolism)
- Fibroma
(etiology, metabolism)
- Gene Expression Regulation, Neoplastic
- Humans
- Immunohistochemistry
- Oligonucleotide Array Sequence Analysis
- Paracrine Communication
(drug effects)
- Rats
- Tuberous Sclerosis
(complications, metabolism)
- Tuberous Sclerosis Complex 2 Protein
- Tumor Cells, Cultured
- Tumor Suppressor Proteins
(genetics, metabolism)
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