Suppression of Ewing's sarcoma tumor growth, tumor vessel formation, and vasculogenesis following anti vascular endothelial growth factor receptor-2 therapy.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
These results indicated that blocking VEGFR-2 with DC101 antibodies may be a useful therapeutic approach for treating patients with Ewing's sarcoma.
Zhou
Zhichao
Z
Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Bolontrade
Marcela F
MF
Reddy
Krishna
K
Duan
Xiaoping
X
Guan
Hui
H
Yu
Ling
L
Hicklin
Daniel J
DJ
Kleinerman
Eugenie S
ES
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement; D042783:Endothelial Cells / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D020286:Pericytes / Q000502:physiology; D051381:Rats; D012512:Sarcoma, Ewing / Q000098:blood supply* / Q000473:pathology / Q000628:therapy*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D000906:Antibodies; D040301:Vascular Endothelial Growth Factor Receptor-2