Fibroblast growth factor receptors-1 and -3 play distinct roles in the regulation of bladder cancer growth and metastasis: implications for therapeutic targeting.

Détails

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Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_FEF6BEA26094
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Fibroblast growth factor receptors-1 and -3 play distinct roles in the regulation of bladder cancer growth and metastasis: implications for therapeutic targeting.
Périodique
PloS one
Auteur(s)
Cheng T., Roth B., Choi W., Black P.C., Dinney C., McConkey D.J.
ISSN
1932-6203 (Electronic)
ISSN-L
1932-6203
Statut éditorial
Publié
Date de publication
2013
Peer-reviewed
Oui
Volume
8
Numéro
2
Pages
e57284
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
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.
Mots-clé
Animals, Base Sequence, Blotting, Western, Cell Division/drug effects, Cell Division/physiology, Cell Line, Tumor, DNA Primers, Female, Gene Expression Profiling, Humans, Mice, Mice, Nude, Mutation, Neoplasm Metastasis, RNA Interference, Real-Time Polymerase Chain Reaction, Receptor, Fibroblast Growth Factor, Type 1/genetics, Receptor, Fibroblast Growth Factor, Type 1/physiology, Receptor, Fibroblast Growth Factor, Type 3/genetics, Receptor, Fibroblast Growth Factor, Type 3/physiology, Reverse Transcriptase Polymerase Chain Reaction, Urinary Bladder Neoplasms/pathology
Pubmed
Web of science
Open Access
Oui
Création de la notice
08/01/2021 16:32
Dernière modification de la notice
30/04/2021 7:16
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