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

Tiewei Cheng, Beat Roth, Woonyoung Choi, Peter C. Black, Colin Dinney, David McConkey

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere57284
JournalPLoS One
Volume8
Issue number2
DOIs
StatePublished - Feb 26 2013
Externally publishedYes

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Receptor, Fibroblast Growth Factor, Type 3
Receptor, Fibroblast Growth Factor, Type 1
Fibroblast Growth Factor Receptors
Urinary Bladder Neoplasms
metastasis
Neoplasm Metastasis
Tumors
therapeutics
Growth
Bearings (structural)
Cells
Vimentin
Cadherins
Therapeutics
Circulating Neoplastic Cells
mutation
Messenger RNA
Mutation
neoplasms
fibroblast growth factor receptor 1

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Fibroblast Growth Factor Receptors-1 and -3 Play Distinct Roles in the Regulation of Bladder Cancer Growth and Metastasis : Implications for Therapeutic Targeting. / Cheng, Tiewei; Roth, Beat; Choi, Woonyoung; Black, Peter C.; Dinney, Colin; McConkey, David.

In: PLoS One, Vol. 8, No. 2, e57284, 26.02.2013.

Research output: Contribution to journalArticle

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