Suppression of Ewing's Sarcoma Tumor Growth, Tumor Vessel Formation, and Vasculogenesis Following Anti–Vascular Endothelial Growth Factor Receptor-2 Therapy

• Published in: Clinical cancer research 2007-08, Vol.13 (16), p.4867-4873
• Main Authors: Zhou, Zhichao, Bolontrade, Marcela F, Reddy, Krishna, Duan, Xiaoping, Guan, Hui, Yu, Ling, Hicklin, Daniel J, Kleinerman, Eugenie S
• Format: Article
• Language: English
• Subjects: Animals; Antibodies - therapeutic use; Antineoplastic agents; Biological and medical sciences; bone marrow cells; Bone Marrow Cells - physiology; Cell Line, Tumor; Cell Movement; Diseases of the osteoarticular system; endothelial cell; Endothelial Cells - physiology; Ewing's sarcoma; Humans; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neovascularization, Pathologic - prevention & control; Pericytes - physiology; Pharmacology. Drug treatments; Rats; Sarcoma, Ewing - blood supply; Sarcoma, Ewing - pathology; Sarcoma, Ewing - therapy; Tumors of striated muscle and skeleton; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; vasculogenesis; VEGF receptor 2 antibody
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-0133

Purpose: We previously showed that bone marrow cells participate in new tumor vessel formation in Ewing's sarcoma, and that vascular endothelial growth factor 165 (VEGF 165 ) is critical to this process. The purpose of this study was to determine whether blocking VEGF receptor 2 (VEGFR-2) with DC101 antibody suppresses tumor growth, reduces tumor vessel formation, and inhibits the migration of bone marrow cells into the tumor. Experimental Design: An H-2 MHC-mismatched bone marrow transplant Ewing's sarcoma mouse model was used. Bone marrow cells from CB6F1 (MHC H-2 b/d ) mice were injected into irradiated BALB/cAnN mice (MHC H-2 d ). TC71 Ewing's sarcoma cells were s.c. injected 4 weeks after the bone marrow transplantation. Mice were then treated i.p. with DC101 antibody or immunoglobulin G (control) twice a week for 3 weeks starting 3 days after tumor cell injection. Results: DC101 antibody therapy significantly reduced tumor growth and tumor mean vessel density ( P < 0.05) and increased tumor cell apoptosis. Decreased bone marrow cell migration into the tumor was also shown after DC101 therapy as assessed by the colocalization of H-2K b and CD31 using immunohistochemistry. DC101 inhibited the migration of both human and mouse vessel endothelial cells in vitro . Conclusion: These results indicated that blocking VEGFR-2 with DC101 antibodies may be a useful therapeutic approach for treating patients with Ewing's sarcoma.