Dominant negative PDGF-C inhibits growth of Ewing family tumor cell lines

Oncogene. 2002 May 30;21(24):3847-54. doi: 10.1038/sj.onc.1205486.


Nearly all cases of Ewing Family Tumors (EFT) harbor chimeric EWS/ETS transcription factors which are thought to aberrantly regulate transcriptional targets of phenotypic consequence. We have recently demonstrated that EWS/ETS proteins up-regulate platelet derived growth factor-C (PDGF-C), a novel transforming growth factor. To determine if PDGF-C signaling contributes to the malignant phenotype of EFT cell lines, we attempted to disrupt this presumed autocrine loop. AG1296, a PDGF receptor selective tyrosine kinase inhibitor, markedly inhibits anchorage-independent growth in an EFT cell line. To effect specific disruption, we have developed a dominant negative form of PDGF-C which is appropriately secreted and processed. This mutant has greatly reduced activity as a PDGF receptor agonist. When co-expressed with PDGF-C in a fibroblast transformation model, this dominant negative dramatically inhibits anchorage-independent growth. When this mutant is expressed in EFT cell lines, there is a similar reduction in anchorage-independent growth. This demonstrates that specific inhibition of PDGF-C signaling in EFT cell lines partially reverts their phenotype. These data support a significant role of PDGF-C in the biology of EFT. They also suggest that PDGF-C driven signaling may be a possible therapeutic target of more clinically relevant tyrosine kinase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Animals
  • Blotting, Western
  • Cell Division
  • Cell Line
  • Dimerization
  • Enzyme Inhibitors / pharmacology
  • Genes, Dominant
  • Green Fluorescent Proteins
  • Humans
  • Luminescent Proteins / metabolism
  • Lymphokines
  • Mice
  • Phenotype
  • Platelet-Derived Growth Factor / genetics*
  • Platelet-Derived Growth Factor / physiology*
  • Precipitin Tests
  • Receptors, Platelet-Derived Growth Factor / metabolism
  • Sarcoma, Ewing / metabolism*
  • Signal Transduction
  • Transfection
  • Tumor Cells, Cultured
  • Up-Regulation


  • Enzyme Inhibitors
  • Luminescent Proteins
  • Lymphokines
  • Platelet-Derived Growth Factor
  • platelet-derived growth factor C
  • Green Fluorescent Proteins
  • Receptors, Platelet-Derived Growth Factor