Evidence for activation of KIT, PDGFRalpha, and PDGFRbeta receptors in the Ewing sarcoma family of tumors.
BACKGROUND
The Ewing sarcoma family of tumors (ESFT) is one of the most common malignant neoplasms of children and adolescents, characterized by nonrandom translocations involving the Ewing sarcoma (EWS) gene. Over the years the adoption of intensive multimodality treatment approaches has led to a gradual improvement in the survival of patients with ESFT. The prognosis is still unsatisfactory for high-risk patients, however, and novel therapeutic approaches are desirable. The aim of the study was to investigate the expression/activation of KIT, PDGFRalpha, and PDGFRbeta receptor tyrosine kinases (RTKs) as potential therapeutic targets in ESFT.


METHODS
RNA and proteins were extracted from 20 frozen ESFT specimens to ascertain the state activation of KIT, PDGFRalpha, and PDGFRbeta.


RESULTS
No mutations were found, whereas the cognate ligands were detected in all cases by polymerase chain reaction (PCR). The expression and activation of KIT, PDGFRalpha, and PDGFRbeta were confirmed by quantitative PCR, immunohistochemistry, and immunoprecipitation and/or Western blot analysis. In particular, when compared with a protein pool obtained from normal adult tissues, PDGFRbeta showed a greater protein expression and/or a stronger phosphorylation signal.


CONCLUSIONS
The results are consistent with an autocrine/paracrine loop activation of the KIT, PDGFRalpha, and PDGFRbeta receptors and suggest a rationale for the use of RTK inhibitors, either alone or in combination with chemotherapy.
Bozzi
Fabio
F
Experimental Molecular Pathology Unit, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori Milan, Italy.
Tamborini
Elena
E
Negri
Tiziana
T
Pastore
Elisa
E
Ferrari
Andrea
A
Luksch
Roberto
R
Casanova
Michela
M
Pierotti
Marco A
MA
Bellani
Franca Fossati
FF
Pilotti
Silvana
S
D000293:Adolescent; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012512:Sarcoma, Ewing / Q000378:metabolism*; D019089:Stem Cell Factor / Q000378:metabolism*
D012333:RNA, Messenger; D019089:Stem Cell Factor; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta