Altered Splicing of FGFR1 Is Associated with High Tumor Grade and Stage and Leads to Increased Sensitivity to FGF1 in Bladder Cancer

Fibroblast growth factor receptors (FGFRs) play key roles in proliferation, differentiation, and tumorigenesis. Previously, we demonstrated that FGFR1 expression is increased in urothelial carcinoma cell lines and tumors, which promotes proliferation and survival via activation of the mitogen-activated protein kinase (MAPK) pathway. Here we examined splice variants of FGFR1 in both urothelial carcinoma cell lines and tumors. Two known FGFR1 IIIc splice variants (FGFR1 alpha and FGFR1 beta) were expressed. FGFR1 beta lacks exon 3 of FGFR1 alpha, removing the first Ig loop of the extracellular domain. Both isoforms were expressed at similar levels in normal urothelial cells, but FGFR1 beta was expressed at higher levels in most tumor cell lines. In tumor tissues, expression levels were higher than in controls, and the FGFR1 beta: FGFR1 alpha ratio was significantly increased in association with tumor stage and grade. When FGFR1 alpha and FGFR1 beta were expressed in urothelial cells, no differences in signaling were observed. FGFR1-induced proliferation paralleled MAPK pathway activation. The relative activation of FGFR1 beta and FGFR1 alpha by all known mammalian FGFs was examined. Both isoforms were activated by the same FGFs, but the level of activation differed. FGFR1 beta showed higher affinity for low concentrations of FGF1, leading to enhanced signaling and increased proliferation. An FGFR1 alpha-to-FGFR1 beta isoform switch and increased FGF1-induced activation of FGFR1 beta may result in a proliferative advantage that plays a key role during bladder tumor progression. (Am J Pathol 2010, 177:2379-2386. DOI: 10.2353/ajpath.2010.100354)