Beta-platelet-derived growth factor receptor mediates motility and growth of Ewing's sarcoma cells Journal Article
| Authors: | Ren, 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. |
| Article Title: | 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 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. |
| Keywords: | immunohistochemistry; signal transduction; controlled study; human tissue; protein expression; protein phosphorylation; bone neoplasms; nonhuman; protein function; mouse; animals; mice; cell division; platelet derived growth factor alpha receptor; cell growth; neoplasm proteins; animal experiment; animal model; drug effect; mice, scid; tumor cells, cultured; drug design; autophosphorylation; phosphorylation; animalia; mus musculus; ewing sarcoma; cancer inhibition; protein processing, post-translational; chemotaxis; nude mouse; enzyme inhibitors; disease progression; recombinant proteins; tumor cell line; 1-phosphatidylinositol 3-kinase; platelet-derived growth factor; ligand; cell migration; neoplasm transplantation; sarcoma, ewing's; cell motility; isoenzymes; platelet derived growth factor beta receptor; phospholipase c gamma; receptor, platelet-derived growth factor beta; protein shc; tyrphostins; ewing's sarcoma; pdgf; 6,7 dimethyl 2 phenylquinoxaline; phospholipase c; platelet derived growth factor bb; humans; human; priority journal; article; pdgf receptors; platelet derived growth factor aa |
| Journal Title: | Oncogene |
| Volume: | 22 |
| Issue: | 15 |
| ISSN: | 0950-9232 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2003-04-17 |
| Start Page: | 2334 |
| End Page: | 2342 |
| Language: | English |
| DOI: | 10.1038/sj.onc.1206330 |
| PUBMED: | 12700668 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 12 September 2014 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work