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, Peter 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
Externally publishedYes

Fingerprint

Platelet-Derived Growth Factor beta Receptor
Platelet-Derived Growth Factor Receptors
Ewing's Sarcoma
Growth
Neoplasms
Platelet-Derived Growth Factor
Chemotaxis
Tumor Cell Line
Cell Movement
Tyrosine
Phosphotransferases
Therapeutics
Animal Models
Cell Culture Techniques
Phosphorylation
Staining and Labeling
Ligands
Cell Line

Keywords

  • Ewing's sarcoma
  • PDGF
  • PDGF receptors

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Üren, A., Merchant, M. S., Sun, C. J., Vitolo, M. I., Sun, Y., Tsokos, M., ... 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

Beta-platelet-derived growth factor receptor mediates motility and growth of Ewing's sarcoma cells. / Üren, A.; Merchant, M. S.; Sun, C. J.; Vitolo, M. I.; Sun, Y.; Tsokos, M.; Illei, Peter B; Ladanyi, M.; Passaniti, A.; Mackall, C.; Toretsky, J. A.

In: Oncogene, Vol. 22, No. 15, 17.04.2003, p. 2334-2342.

Research output: Contribution to journalArticle

Üren, A, Merchant, MS, Sun, CJ, Vitolo, MI, Sun, Y, Tsokos, M, Illei, PB, Ladanyi, M, Passaniti, A, Mackall, C & Toretsky, JA 2003, 'Beta-platelet-derived growth factor receptor mediates motility and growth of Ewing's sarcoma cells', Oncogene, vol. 22, no. 15, pp. 2334-2342. https://doi.org/10.1038/sj.onc.1206330
Üren A, Merchant MS, Sun CJ, Vitolo MI, Sun Y, Tsokos M et al. Beta-platelet-derived growth factor receptor mediates motility and growth of Ewing's sarcoma cells. Oncogene. 2003 Apr 17;22(15):2334-2342. https://doi.org/10.1038/sj.onc.1206330
Üren, A. ; Merchant, M. S. ; Sun, C. J. ; Vitolo, M. I. ; Sun, Y. ; Tsokos, M. ; Illei, Peter B ; Ladanyi, M. ; Passaniti, A. ; Mackall, C. ; Toretsky, J. A. / Beta-platelet-derived growth factor receptor mediates motility and growth of Ewing's sarcoma cells. In: Oncogene. 2003 ; Vol. 22, No. 15. pp. 2334-2342.
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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.",
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AU - Tsokos, M.

AU - Illei, Peter B

AU - Ladanyi, M.

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AU - Mackall, C.

AU - Toretsky, J. A.

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