Clin Cancer Res. 2005 Mar 15;11(6):2364-2378.
Vascular Endothelial Growth Factor: A Therapeutic Target for Tumors of
the Ewing's Sarcoma Family.
Dalal S, Berry AM, Cullinane CJ, Mangham DC, Grimer R, Lewis IJ,
Johnston C, Laurence V, Burchill SA.
Candlelighter's Children's Cancer Research Laboratory, Departments of
Pathology and Paediatric Oncology, Cancer Research UK Clinical Centre,
St. James's University Hospital, Leeds, United Kingdom and Department of
Musculoskeletal Pathology and Royal Orthopaedic Hospital, Birmingham,
United Kingdom.
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-beta, 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.
PMID: 15788688 [PubMed – as supplied by publisher]