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Regulation of Fibroblast Growth Factor-2 Activity by Human Ovarian Cancer Tumor Endothelium

Authors' Affiliations: ¹ Cancer Research UK Department of Medical Oncology, Christie Hospital and Paterson Institute; ² Department of Histopathology, Manchester Royal Infirmary; ³ School of Environment and Life Sciences, University of Salford; ⁴ Department of Gynaecological Oncological Surgery, Christie Hospital, Manchester, United Kingdom; ⁵ Department of Pathology and Laboratory Medicine, Medical Sciences Center, University of Wisconsin-Madison, Madison, Wisconsin; and ⁶ Centre for Human Genetics, University of Leuven, Leuven, Belgium

Requests for reprints: Gordon C. Jayson, Cancer Research UK Department of Medical Oncology, Christie Hospital, Wilmslow Road, Manchester M20 4BX, United Kingdom. Phone: 44-161-446-3606; Fax: 44-161-446-3461; E-mail: Gordon.Jayson{at}christie-tr.nwest.nhs.uk or GordonJayson{at}aol.com.

Fibroblast growth factor-2 (FGF-2) is a potent 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 FGF receptor 1 isoform lllc 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 stroma but was absent from adenocarcinoma 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 antiangiogenic treatment of this disease.

Key Words: Angiogenesis • FGF-2 • heparan sulfate

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