Beta-platelet-derived growth factor receptor mediates motility and growth of Ewing's sarcoma cells

A. Üren, M. S. Merchant, C. J. Sun, M. I. Vitolo, Y. Sun, M. Tsokos, P. B. Illei, M. Ladanyi, A. Passaniti, C. Mackall, J. A. Toretsky

Research output: Contribution to journalArticle

Abstract

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 β-PDGFR. Interestingly, none of the tested cell lines expressed α-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 β-PDGFR. ESFT cell lines were treated with PDGF-AA or PDGF-BB ligands to evaluate downstream signaling. Autophosphorylation of β-PDGFR and tyrosine phosphorylation of PLC-γ, PI3Kp85 and Shc were detected only in PDGF-BB-stimulated cells that express β-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 β-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 β-PDGFR and that this is a functional and potentially crucial signaling pathway. Therefore, β-PDGFRs may provide a novel therapeutic target in ESFT that can be utilized to design better treatment modalities.

Original languageEnglish (US)
Pages (from-to)2334-2342
Number of pages9
JournalOncogene
Volume22
Issue number15
DOIs
StatePublished - Apr 17 2003

Keywords

  • Ewing's sarcoma
  • PDGF
  • PDGF receptors

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Üren, 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. (2003). Beta-platelet-derived growth factor receptor mediates motility and growth of Ewing's sarcoma cells. Oncogene, 22(15), 2334-2342. https://doi.org/10.1038/sj.onc.1206330