The endogenous anti-angiogenic VEGF isoform, VEGF165b inhibits human tumour growth in mice.
Vascular endothelial growth factor-A is widely regarded as the principal stimulator of angiogenesis required for tumour growth. VEGF is generated as multiple isoforms of two families, the pro-angiogenic family generated by proximal splice site selection in the terminal exon, termed VEGFxxx, and the anti-angiogenic family formed by distal splice site selection in the terminal exon, termed VEGFxxxb, where xxx is the amino acid number. The most studied isoforms, VEGF165 and VEGF165b have been shown to be present in tumour and normal tissues respectively. VEGF165b has been shown to inhibit VEGF- and hypoxia-induced angiogenesis, and VEGF-induced cell migration and proliferation in vitro. Here we show that overexpression of VEGF165b by tumour cells inhibits the growth of prostate carcinoma, Ewing's sarcoma and renal cell carcinoma in xenografted mouse tumour models. Moreover, VEGF165b overexpression inhibited tumour cell-mediated migration and proliferation of endothelial cells. These data show that overexpression of VEGF165b can inhibit growth of multiple tumour types in vivo indicating that VEGF165b has potential as an anti-angiogenic, anti-tumour strategy in a number of different tumour types, either by control of VEGF165b expression by regulation of splicing, overexpression of VEGF165b, or therapeutic delivery of VEGF165b to tumours.
Rennel
Es
E
Microvascular Research Laboratories, Department of Physiology and Pharmacology, School of Veterinary Science, University of Bristol, Southwell Street, Bristol BS2 8EJ, UK.
Waine
E
E
Guan
H
H
Schüler
Y
Y
Leenders
W
W
Woolard
J
J
Sugiono
M
M
Gillatt
D
D
Kleinerman
Es
E
Bates
Do
D
Harper
Sj
S
D017398:Alternative Splicing; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology*; D009389:Neovascularization, Pathologic; D011467:Prostate / Q000166:cytology / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000473:pathology; D020033:Protein Isoforms; D012512:Sarcoma, Ewing / Q000473:pathology; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000494:pharmacology*
D020033:Protein Isoforms; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A