VEGF(165), but not VEGF(189), stimulates vasculogenesis and bone marrow cell migration into Ewing's sarcoma tumors in vivo.
We previously showed that bone marrow stem cells participate in the tumor vessel expansion that supports the growth of Ewing's sarcoma tumors in vivo. The purpose of this study was to determine the relative importance of two isoforms of vascular endothelial growth factor (VEGF) in tumor vessel expansion and recruitment of bone marrow-derived cells during tumor growth. We injected VEGF(165)-siRNA-transfected cells (TCsi/7-1), control siRNA-transfected cells (TC/si-control), or TC71 parental Ewing's sarcoma cells into nude mice. The TCsi/7-1 tumors were then treated with adenoviral vectors expressing VEGF(165) (Ad-VEGF(165)), VEGF(189) (Ad-VEGF(189)), or beta-galactosidase (Ad-beta-gal). Bone marrow cells labeled with fluorescent tracker dye were injected into the mice 3 weeks later. The TCsi/7-1 tumors were significantly smaller (P < 0.05), had decreased vessel density, and showed significantly lower bone marrow cell migration than did TC71 parental and TC/si-control tumors. Treatment with Ad-VEGF(165), but not Ad-VEGF(189) or Ad-beta-gal, resulted in a significant increase in bone marrow cell infiltration, tumor vessel density, and tumor growth. Immunohistochemical staining revealed that the injected bone marrow cells migrated to and incorporated into the expanding CD31(+) tumor vessel network. Taken together, these data show that VEGF(165) is a chemoattractant that recruits bone marrow cells into the tumor area. These data provide a mechanism by which Ewing's sarcoma cells induce vasculogenesis.
Zhou
Zhichao
Z
Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Unit 87, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Reddy
Krishna
K
Guan
Hui
H
Kleinerman
Eugenie S
ES
D000818:Animals; D001854:Bone Marrow Cells; D001859:Bone Neoplasms / Q000098:blood supply*; D002465:Cell Movement; D042783:Endothelial Cells; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D012512:Sarcoma, Ewing / Q000098:blood supply*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D020033:Protein Isoforms; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A