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

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

JOURNAL OF UROLOGY

ELSEVIER SCIENCE INC

Año: 2015

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 variation of FGF-2 and fibroblast growth factor receptors (FGFRs) expression in BCG anti-tumor activity.Outcome Measurements and Statistical Analysis: Student´s T-test, Mann-Whitney, ANOVA and Kruskal-Wallys analysis were used.Results: In vitro, FGF-2 is produced by MB49 cells. It induced cell proliferation, but was not able to reverse BCG-induced cell death. 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 decrease 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 produced a down-regulation of FGFR3 in about 41% of cases.Conclusion: In spite BCG induces FGF-2 production, the down-regulation of FGFR3 in tumor cells is associated with murine tumor growth inhibition. T24 cells and a large percentage of human bladder tumors showed decreased in FGFR3 expression after BCG treatment. FGFR3 down-regulation in response to BCG could identify patients suitable to this therapy and should be studied as a prognostic marker of response in patients that relapse to immunotherapy.