Regulation of fibroblast growth factor-2 activity by human ovarian cancer tumor endothelium

Melissa K. Whitworth, Alison C. Backen, Andrew R. Clamp, Godfrey Wilson, Rhona Mc Vey, Andreas Friedl, Alan C. Rapraeger, Guido David, Alan McGown, Richard J. Slade, John T. Gallagher, Gordon C. Jayson

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Fibroblast growth factor-2 (FGF-2) is a piotent angiogenic cytokine that is dependent on heparan sulfate for its biological activity. We have investigated the relationship among heparan sulfate, FGF-2, and the signal-transducing receptors in human, advanced-stage, serous ovarian adenocarcinoma. Using a unique molecular probe, FR1c-Ap, which consisted of a soluble PGF receptor 1 isoform IIIc covalently linked to an alkaline phosphatase moiety, the distribution of heparan sulfate that had the ability to support the formation of a heparan sulfate/FGF-2/FGFR1 isoform IIIc alkaline phosphatase heparan sulfate construct complex was determined. This may be taken as a surrogate marker for the distribution of biologically active heparan sulfate and was distributed predominantly in endothelial cells and strorria but was absent from adenocarcihoma cells. In situ hybridization revealed the expression of FGFR1 mRNA in the endothelium and reverse transcription-PCR confirmed the presence of FGFR1 isoform IIIc but not isoform IIIb. The presence of FGF-2 around tumor endothelium was detected through immunohistochemistry. Double-staining techniques showed that heparan sulfate was found predominantly at the basal aspect of the endothelium and suggested that syndecan-3 might function as one of the proteoglycans involved in FGF-2 signaling in the endothelium. The data suggest that the entire extracellular signaling apparatus, consisting of FGF-2, biologically active heparan sulfate, and FGFRs capable of responding to FGF-2, is present in ovarian cancer endothelium, thereby highlighting the cytokine and its cognate receptor as potential targets for the antiangiogeriic treatment of this disease. © 2005 American Association for Cancer Research.
    Original languageEnglish
    Pages (from-to)4282-4288
    Number of pages6
    JournalClinical Cancer Research
    Volume11
    Issue number12
    DOIs
    Publication statusPublished - 15 Jun 2005

    Keywords

    • metabolism: Alkaline Phosphatase
    • chemistry: Endothelium
    • Female
    • metabolism: Fibroblast Growth Factor 2
    • Gene Expression Regulation, Neoplastic
    • metabolism: Heparitin Sulfate
    • Humans
    • methods: Immunohistochemistry
    • In Situ Hybridization
    • genetics: Ovarian Neoplasms
    • genetics: Protein Isoforms
    • genetics: RNA, Messenger
    • genetics: Receptor Protein-Tyrosine Kinases
    • genetics: Receptors, Fibroblast Growth Factor
    • Research Support, Non-U.S. Gov't
    • Reverse Transcriptase Polymerase Chain Reaction
    • metabolism: Sulfates

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