Fibroblast Growth Factor Receptor 1 Promotes Proliferation and Survival via Activation of the Mitogen-Activated Protein Kinase Pathway in Bladder Cancer

Abstract

Fibroblast growth factor receptors (FGFR) play key roles in proliferation, differentiation, and tumorigenesis. Many urothelial carcinomas contain activating point mutations or increased expression of FGFR3. However, little is known about the role of other FGFRs. We examined FGFR expression in telomerase-immortalized normal human urothelial cells, urothelial carcinoma cell lines, and tumor samples and showed that FGFR1 expression is increased in a high proportion of cell lines and tumors independent of stage and grade. To determine the role of FGFR1 in low-stage bladder cancer, we overexpressed FGFR1 in telomeraseimmortalized normal human urothelial cells and examined changes in proliferation and cell survival in response to FGF2. FGFR1 stimulation increased proliferation and reduced apoptosis. To elucidate the mechanistic basis for these alterations, we examined the signaling cascades activated by FGFR1. FRS2A and PLC; were activated in response to FGF2, leading to activation of the mitogen-activated protein kinase pathway. The level of mitogen-activated protein kinase activation correlated with the level of cyclin D1, MCL1, and phospho-BAD, which also correlated with FGFR-induced proliferation and survival. Knockdown of FGFR1 in urothelial carcinoma cell lines revealed differential FGFR1 dependence. JMSU1 cells were dependent on FGFR1 expression for survival but three other cell lines were not. Two cell lines (JMSU1 and UMUC3) were dependent on FGFR1 for growth in soft agar. Only one of the cell lines tested (UMUC3) was frankly tumorigenic; here, FGFR1 knockdown inhibited tumor growth. Our results indicate that FGFR1 has significant effects on urothelial cell phenotype and may represent a useful therapeutic target in some cases of urothelial carcinoma.

Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy

“…42 As a protein assayed by IHC, FGFR1 is frequently overexpressed in urothelial carcinoma, and has been associated with MAPK pathway activation and the epithelial-mesenchymal transition. [43][44][45] Three UCs in this series featured FGFR1 amplifications, consistent with FGFR1 being commonly amplified in human cancers, and has been previously reported in approximately 3% of UCs. 39,45 FGFR mRNA overexpression has also been reported in UC.…”

Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer

“…The traditional somatic genetic basis of TCC-UB is a distinct division of low-grade papillary tumors from high-grade invasive tumors. Low-grade papillary superficial tumors are generally characterized by constitutive activation of the receptor tyrosine kinase-Ras pathway, and they have activating mutations in the HRAS and fibroblast growth factor receptor 3 (FGFR3) genes (3)(4)(5)(6). In contrast, high-grade invasive TCC-UB is characterized by alterations in the tumor protein p53 (TP53) and retinoblastoma 1 (RB1) pathways.…”

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

“…[15][16][17] FGFRs may also prove to be valid therapeutic targets in invasive disease. A high proportion of invasive tumors express high levels of FGFR1, 18 and many show up-regulation of nonmutant FGFR3. 19 Activation of FGFR1 led to increased proliferation and decreased apoptosis in normal urothelial cells and knockdown of FGFR1 in bladder cancer cell lines demonstrated that some lines depended on FGFR1 for survival and cell proliferation in vitro and in vivo.…”