| Autor: |
Uren, A, Merchant, M S, Sun, C J, Vitolo, M I, Sun, Y, Tsokos, M, Illei, P B, Ladanyi, M, Passaniti, A, Mackall, C, Toretsky, J A |
| Předmět: |
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| Zdroj: |
Oncogene; 4/17/2003, Vol. 22 Issue 15, p2334, 9p |
| Abstrakt: |
The Ewing's sarcoma family of tumors (ESFT) contain a translocation, t(11;22), which results in the novel oncogenic fusion protein EWS/FLI1. Platelet-derived growth factors (PDGF) and their receptors (PDGFR) are involved in the induction and proliferation of numerous solid tumors and are the potential candidates for novel targeted antitumor therapy. Since a relation was reported between PDGF-C and EWS/FLI1, we sought to characterize the PDGF signaling pathway in ESFT. Eight out of nine ESFT cell lines were found to express significant levels of ?-PDGFR. Interestingly, none of the tested cell lines expressed a-PDGFR, which is the receptor isotype required for PDGF-C binding. By immunohistochemical staining 47 of 52 (90.4%) archival tumor samples from patients with ESFT were positive for ?-PDGFR. ESFT cell lines were treated with PDGF-AA or PDGF-BB ligands to evaluate downstream signaling. Autophosphorylation of ?-PDGFR and tyrosine phosphorylation of PLC-?, PI3Kp85 and Shc were detected only in PDGF-BB-stimulated cells that express ?-PDGFR. Receptor function was further evaluated using chemotaxis assays that showed TC-32 cell migration towards PDGF-BB. A specific PDGFR kinase inhibitor AG1295 blocked ?-PDGFR activation, downstream signaling, growth in cell culture and chemotaxis of TC-32 cells. AG1295 also delayed tumor formation and prolonged survival in an ESFT animal model. We conclude that ESFT express ?-PDGFR and that this is a functional and potentially crucial signaling pathway. Therefore, ?-PDGFRs may provide a novel therapeutic target in ESFT that can be utilized to design better treatment modalities.Oncogene (2003) 22, 2334-2342. doi:10.1038/sj.onc.1206330 [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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