Fibroblast Growth Factor Receptors-1 and -3 Play Distinct Roles in the Regulation of Bladder Cancer Growth and Metastasis: Implications for Therapeutic Targeting

Abstract

Fibroblast growth factor receptors (FGFRs) are activated by mutation and overexpressed in bladder cancers (BCs), and FGFR inhibitors are currently being evaluated in clinical trials in BC patients. However, BC cells display marked heterogeneity in their responses to FGFR inhibitors, and the biological mechanisms underlying this heterogeneity are not well defined. Here we used a novel inhibitor of FGFRs 1–3 and RNAi to determine the effects of inhibiting FGFR1 or FGFR3 in a panel of human BC cell lines. We observed that FGFR1 was expressed in BC cells that also expressed the “mesenchymal” markers ZEB1 and vimentin, whereas FGFR3 expression was restricted to the E-cadherin- and p63-positive “epithelial” subset. Sensitivity to the growth-inhibitory effects of BGJ-398 was also restricted to the “epithelial” BC cells and it correlated directly with FGFR3 mRNA levels but not with the presence of activating FGFR3 mutations. In contrast, BGJ-398 did not strongly inhibit proliferation but did block invasion in the “mesenchymal” BC cells in vitro. Similarly, BGJ-398 did not inhibit primary tumor growth but blocked the production of circulating tumor cells (CTCs) and the formation of lymph node and distant metastases in mice bearing orthotopically implanted “mesenchymal” UM-UC3 cells. Together, our data demonstrate that FGFR1 and FGFR3 have largely non-overlapping roles in regulating invasion/metastasis and proliferation in distinct “mesenchymal” and “epithelial” subsets of human BC cells. The results suggest that the tumor EMT phenotype will be an important determinant of the biological effects of FGFR inhibitors in patients.

Meta-Analysis of the Luminal and Basal Subtypes of Bladder Cancer and the Identification of Signature Immunohistochemical Markers for Clinical Use

“…Other studies have identified distinct genomic signatures associated with cancer progression, metastasis and response to therapeutic manipulations (Takata et al, 2005, Puzio-Kuter et al, 2009, Cheng et al, 2013, Van Allen et al, 2014, Groenendijk et al, 2016, Dyrskjot et al, 2003). Several groups used whole genome expression profiling to classify bladder cancer into various distinct subtypes (Cancer Genome Atlas Research N, 2014, Damrauer et al, 2014, Choi et al, 2014a, Lindgren et al, 2010, Sjodahl et al, 2012).…”

Fibroblast Growth Factor Receptor 3 Interacts with and Activates TGFβ-Activated Kinase 1 Tyrosine Phosphorylation and NFκB Signaling in Multiple Myeloma and Bladder Cancer

“…In all lines, whether expressing wild-type or mutant FGFR3, we observed significantly reduced NFκB activation following knockdown of TAK1 (Figures 4 B, C). Addition of ligand enhanced this effect in MGHU3 cells, likely by activating other FGF receptors [42]. As a final test of NFκB activation, nuclear localization of the active p65 subunit of NFκB was evaluated.…”

Fibroblast growth factor receptor 1 and cytokeratin 20 expressions and their relation to prognostic variables in bladder cancer

“…Yet, they found no relationship between FGFR1 expression level and stage or grade (Tomlinson et al, 2009). Cheng et al (2013) demonstrated that FGFR1 has an important role in regulating proliferation and invasion/metastasis in "mesenchymal" and "epithelial" cells of human cancer bladder cells. By the contrary, Fischbach et al (2015) reported that amplifications of FGFR1 were found in only 1.6% of bladder cancer patients and FGFR amplifications are rare events in bladder cancer.…”