FGFR3 down-regulation is involved in BCG bladder tumor growth inhibition

LANGLE, YANINA; BELGOROSKY, DENISE; PRACK MC CORMICK, BÁRBARA; SAHORES, ANA; GÓNGORA, ADRIÁN; BALDI, ALBERTO; LANARI, CLAUDIA; LAMB, CAROLINE A.; EIJÁN, ANA MARÍA

JOURNAL OF UROLOGY

ELSEVIER SCIENCE INC

Lugar: Philadelphia; Año: 2016

0022-5347

Background: Bacillus Calmette-Guerin (BCG) is the standard treatment for patients with non-muscle invasive high histological grade bladder cancer (BC). Previously, we have demonstrated that BCG induces murine BC MB49 cell death both in vitro and in vivo, generating tissue remodeling, which involves the release of fibroblast growth factor 2 (FGF-2).Objective: To study the effect of BCG treatment in FGF-2 and fibroblast growth factor receptors (FGFRs) expression in bladder cancer.Outcome Measurements and Statistical Analysis: Student´s T-test, Mann-Whitney, ANOVA and Kruskal-Wallys analysis were used.Results: In vitro, FGF-2 induced cell proliferation of MB49 cells, but was not able to reverse BCG-induced cell death. An increased expression of FGF-2 was detected after BCG treatment. Moreover, MB49 cells expressed low levels of FGFR2 and high membrane and nuclear levels of FGFR3, both of which decreased after BCG treatment. In vivo, normal murine bladder urothelium expressed low FGFR1-2 and high FGFR3 levels, whereas MB49 tumors expressed only high nuclear levels of FGFR3, which decreased after BCG treatment. This reduction correlates with the inhibition of tumor growth in response to BCG. Human T24 BC cells expressed membrane and nuclear FGFR3, which decreased after BCG treatment. Ex vivo treatment with BCG of human bladder tumors induced FGFR3 down-regulation in approximately 41% of cases.Conclusion: The down-regulation of FGFR3 in tumor cells is associated with murine tumor growth inhibition despite BCG-induced FGF2 expression, T24 cells and 41% of human bladder tumors showed a reduction in FGFR3 expression after BCG treatment. FGFR3 downregulation in response to BCG treatment identified patients suitable for this therapy. We propose FGFR3 as a predictive marker of response to BCG treatment in patients that relapse after immunotherapy.