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Fibroblast Growth Factor Receptor 3 Is Overexpressed in Urinary Tract Carcinomas and Modulates the Neoplastic Cell Growth

¹ Departamento Anatomá Patológica Servicio de ² Urologa and ³ Oncologa Médica, Hospital Universitario "Marqués de Valdecilla" Servicio Cántabro de Salud, Facultad de Medicina, Universidad de Cantabria. Santander, Spain, and ⁴ Progenika, SA Medplant Genetics, S.L. Parque Tecnológico de Zamudio, Derio, Vizcaya, Spain

Requests for reprints: J. Fernando Val-Bernal, Departamento de Anatoma Patológica. Hospital Universitario "Marqués de Valdecilla," Avenida de Valdecilla s/n E39008 Santander, Cantabria, Spain. Phone: 34-94-220-2599; Fax: 34-94-220-3492; E-mail: apavbj{at}humv.es.

Purpose: Fibroblast growth factor receptor 3 (FGFR3) mutations have been associated with achondroplastic syndromes and urinary bladder carcinomas. Here we describe changes in FGFR3 mRNA and protein expression in transitional carcinomas and determine the effect of monoclonal antibodies against FGFR3 in RT-112 cell line proliferation.

Experimental Design: We used microarray tools to evaluate FGFR3 mRNA expression in 22 urinary bladder carcinomas at different stages (noninvasive pTa, lamina propria invasive pT1, and muscular invasive pT2) and 7 nonneoplastic tissue controls. FGFR3 protein expression was evaluated by Western blotting in 15 different carcinomas and 3 nonneoplastic controls. Two hundred thirty-seven urinary bladder and renal pelvis carcinomas and 21 negative controls were tested on tissue microarrays by immunohistochemistry. The effect on cell proliferation in the RT-112 bladder cancer cell line of monoclonal antibodies against FGFR3 was also evaluated.

Results: Overexpression of FGFR3 mRNA was found in pTa and pT1 stage carcinomas (fold change >8) and in pT2 carcinomas (fold change >4). Nonneoplastic urinary bladder samples do not express FGFR3 protein. However, 83% of pTa, 100% of pT1, and 50% of pT2 carcinomas expressed FGFR3 as determined by Western blotting. By immunohistochemistry, FGFR3 was positive in 71.4% of pTa, 72% of pT1, and 49.2% of pT2 cases as well as 61.5% of upper urinary tract carcinomas. Proliferation of the RT-112 cell line was inhibited with monoclonal antibodies against FGFR3.

Conclusions: FGFR3 seems to play an important role in transitional cell carcinoma development. Our results suggest that FGFR3 antagonists could be developed as possible therapeutics for treatment of urinary tract carcinoma.

Key Words: FGFR3 • Transitional carcinoma • Urinary bladder

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