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Vascular Endothelial Growth Factor: A Therapeutic Target for Tumors of the Ewing's Sarcoma Family

¹ Candlelighter's Children's Cancer Research Laboratory, Departments of ² Pathology and ³ Paediatric Oncology, ⁴ Cancer Research UK Clinical Centre, St. James's University Hospital, Leeds, United Kingdom and ⁵ Department of Musculoskeletal Pathology and ⁶ Royal Orthopaedic Hospital, Birmingham, United Kingdom

Requests for reprints: Surita Dalal, Candlelighter's Children's Cancer Research Laboratory, Cancer Research UK Clinical Centre, St. James's University Hospital, Leeds LS9 7TF, West Yorkshire, United Kingdom. Phone: 44-113-2064922/4912; Fax: 44-113-2429886; E-mail: s.dalal{at}cancermed.leeds.ac.uk.

Purpose: We have reported previously that intratumoral microvessel density (MVD) is a significant prognostic indicator of event-free survival in the Ewing's sarcoma family of tumors (ESFT). Here, the angiogenic growth factor expression profile and its relationship with MVD has been investigated in ESFT.

Experimental Design and Results: Using ESFT model systems, the potential of these factors as therapeutic targets has been evaluated. A significant correlation (P = 0.02) was observed between vascular endothelial growth factor (VEGF) expression and MVD, consistent with the hypothesis that VEGF regulates the development of microvessels in ESFT. There was no correlation between MVD and any of the other growth factors studied. All six ESFT cell lines studied produced and secreted VEGF; five of six cell lines also secreted placental growth factor, one cell line (A673) at high levels. Tumor conditioned medium induced proliferation of human umbilical vein endothelial cells. Expression of VEGF receptors Flt-1 and Flk-1/KDR was heterogeneous across the cell lines. Both receptor tyrosine kinase inhibitors SU6668 (targets Flk-1/KDR, platelet-derived growth factor receptor-ß, and fibroblast growth factor receptor 1) and SU5416 (targets Flk-1/KDR) as well as anti-VEGF agents rhuMAb-VEGF (bevacizumab) and VEGF Trap delayed s.c. growth of ESFT in mice compared with untreated groups: SU6668 (100 mg/kg/d), SU5416 (25 mg/kg/d), rhuMAb-VEGF (10 mg/kg twice weekly), and VEGF Trap (2.5 or 25 mg/kg twice weekly).

Conclusions: These data suggest that VEGF is the single most important regulator of angiogenesis in ESFT and may be exploited for therapeutic advantage.

Key Words: Tumor Angiogenesis • vascular endothelial growth factor • micro-vessel density • Pediatric cancers • Sarcoma/soft-tissue malignancies • CELLULAR, MOLECULAR, AND TUMOR BIOLOGY • Angiogenic factors and receptors

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