Oncogenic properties of the mutated forms of fibroblast growth factor receptor 3b.
Germinal activating mutations of FGFR3 are responsible for several forms of dwarfism due to the inhibitory effect of FGFR3 on bone growth. Surprisingly, identical somatic activating mutations have been found at the somatic level in tumours: at high frequency in benign epithelial tumours (seborrheic keratosis, urothelial papilloma) and in low-grade, low-stage urothelial carcinomas, and at a lower frequency in other types of urothelial carcinoma, in cervix carcinoma, and in haematological cancer, multiple myeloma. FGFR3 exists as two isoforms, FGFR3b and FGFR3c, differs in ligand specificity and tissue expression. FGFR3b is the main form in epithelial cells and derived tumours, whereas FGFR3c is the main form in mesenchyme-derived cells and multiple myeloma. Several lines of evidence suggest that mutated FGFR3c has transforming properties. Although mutated FGFR3b is mostly found in benign epithelial tumours or carcinomas of low malignant potential, we present evidence here that mutated FGFR3b is oncogenic. All bladder tumours presenting FGFR3 mutations expressed this receptor more strongly than normal urothelium or non-mutated tumours. NIH-3T3 cells transfected with a mutated form of FGFR3b--FGFR3b-S249C, the most common mutation in bladder tumours--presented a spindle-cell morphology, grew in soft agar and gave rise to tumours when xenografted into nude mice. We identified one line of 17 bladder cell lines tested (MGH-U3) that expressed a mutated form of FGFR3b, FGFR3b-Y375C. We showed using siRNA and SU5402, an FGFR inhibitor, that the tumour properties of MGH-U3 depended on mutated receptor activity. Thus, in two different models, mutated FGFR3b presents oncogenic properties.
Bernard-Pierrot
Isabelle
I
UMR 144, CNRS-Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, and INSERM 0337 and Service d'Urologie, Centre Hospitalier Universitaire Henri Mondor, AP-HP, Université Paris XII, 94010 Créteil Cedex, France.
Brams
Aude
A
Dunois-Lardé
Claire
C
Caillault
Aurélie
A
Diez de Medina
Sixtina Gil
SG
Cappellen
David
D
Graff
Gabriel
G
Thiery
Jean Paul
JP
Chopin
Dominique
D
Ricol
David
D
Radvanyi
François
F
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004252:DNA Mutational Analysis; D004847:Epithelial Cells; D005260:Female; D005347:Fibroblasts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020033:Protein Isoforms; D011758:Pyrroles / Q000494:pharmacology; D034741:RNA, Small Interfering; D051498:Receptor, Fibroblast Growth Factor, Type 3; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014183:Transplantation, Heterologous; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000503:physiopathology
D020033:Protein Isoforms; D011758:Pyrroles; D034741:RNA, Small Interfering; C105686:SU 5402; D051498:Receptor, Fibroblast Growth Factor, Type 3