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

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

• Authors: A Uren, 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
• Journal: Oncogene (Oncogene) Vol. 22 Issue 15 Pg. 2334-42 (Apr 17 2003) ISSN: 0950-9232 [Print] England
• PMID: 12700668 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 6,7-dimethoxy-2-phenylquinoxaline
• Enzyme Inhibitors
• Isoenzymes
• Neoplasm Proteins
• Platelet-Derived Growth Factor
• Proto-Oncogene Proteins c-sis
• Recombinant Proteins
• Tyrphostins
• platelet-derived growth factor A
• Becaplermin
• Phosphatidylinositol 3-Kinases
• Class Ib Phosphatidylinositol 3-Kinase
• PIK3CG protein, human
• Pik3cg protein, mouse
• Receptor, Platelet-Derived Growth Factor beta
• Type C Phospholipases
• Phospholipase C gamma

Topics

• Animals
• Becaplermin
• Bone Neoplasms (metabolism, pathology)
• Cell Division (drug effects)
• Chemotaxis (drug effects)
• Class Ib Phosphatidylinositol 3-Kinase
• Disease Progression
• Enzyme Inhibitors (pharmacology)
• Humans
• Isoenzymes (metabolism)
• Mice
• Mice, SCID
• Neoplasm Proteins (biosynthesis, genetics, physiology)
• Neoplasm Transplantation
• Phosphatidylinositol 3-Kinases (metabolism)
• Phospholipase C gamma
• Phosphorylation (drug effects)
• Platelet-Derived Growth Factor (pharmacology)
• Protein Processing, Post-Translational (drug effects)
• Proto-Oncogene Proteins c-sis
• Receptor, Platelet-Derived Growth Factor beta (biosynthesis, drug effects, genetics, physiology)
• Recombinant Proteins (pharmacology)
• Sarcoma, Ewing (metabolism, pathology)
• Signal Transduction (drug effects)
• Tumor Cells, Cultured (cytology, metabolism)
• Type C Phospholipases (metabolism)
• Tyrphostins (pharmacology)