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    Inhibition of FGFR2 and FGFR1 increases cisplatin sensitivity in ovarian cancer.

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    Authors
    Cole, Claire L
    Lau, Sin
    Backen, Alison C
    Clamp, Andrew R
    Rushton, Graham
    Dive, Caroline
    Hodgkinson, Cassandra L
    McVey, Rhona J
    Kitchener, Henry C
    Jayson, Gordon C
    Affiliation
    Cancer Research UK and University of Manchester Dept. Translational Angiogenesis, Paterson Institute, Withington, Manchester, UK. ccole@picr.man.ac.uk.
    Issue Date
    2010-09-04
    
    Metadata
    Show full item record
    Abstract
    Fibroblast Growth Factors (FGFs) have been implicated in malignant transformation, tumor mitogenesis, angiogenesis and chemoresistance. The aim of this study was to determine which FGFs and FGFRs play functional roles in epithelial ovarian cancer. Restriction enzyme analysis of mRNA revealed that transformation was associated with a switch in FGFR2 and FGFR3, from the IIIc to the IIIb isoform. There was widespread expression of FGFs, including FGF7, in all tissues but, FGF3 and FGF19 were expressed by malignant cell lines and cancer tissue but were not present in normal tissue. Using FGFR-specific shRNAi we demonstrated that reductions in FGFR2 inhibited proliferation of ovarian cancer cell lines in vitro (>50%, p < 0.006) and reduced cisplatin IC(50) (>60%, p < 0.0001). Cell cycle analysis revealed increased cisplatin sensitivity was associated with increased G(2)/M arrest and increased apoptosis. FGFR2 shRNAi reduced growth rates of ovarian tumor xenografts by 20% (p > 0.006) and when combined with cisplatin caused a 40% reduction in proliferation rates (p < 0.007). In contrast, RNAi-induced reductions in FGFR1 increased SKOV3 cell numbers, with associated changes in cell cycle but had no effect on ES2 cells. However, the cisplatin IC(50) was reduced (>50%, p < 0.0001) by FGFR1 shRNAi in both cell lines and there was increased apoptosis (46-50%) compared with control cells (35%) (p > 0.004). Together our data suggest that combining FGFR2 inhibitors with platinum-containing cytotoxic agents for the treatment of epithelial ovarian cancer may yield increased anti-tumor activity. However, data on the inhibition of FGFR1 suggest that broad spectrum FGFR inhibitors may have unexpected effects on proliferation.
    Citation
    Inhibition of FGFR2 and FGFR1 increases cisplatin sensitivity in ovarian cancer. 2010, 10 (5):notCancer Biol Ther
    Journal
    Cancer Biology & Therapy
    URI
    http://hdl.handle.net/10541/111178
    DOI
    10.4161/cbt.10.5.12585
    PubMed ID
    20595807
    Type
    Article
    Language
    en
    ISSN
    1555-8576
    ae974a485f413a2113503eed53cd6c53
    10.4161/cbt.10.5.12585
    Scopus Count
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    All Christie Publications
    All Paterson Institute for Cancer Research

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