VEGF121b, a new member of the VEGFxxxb family of VEGF-A splice isoforms, inhibits neovascularisation and tumour growth in vivo

• Published in: British journal of cancer 2009-10, Vol.101 (7), p.1183-1193
• Main Authors: Rennel, E S, Varey, A H R, Churchill, A J, Wheatley, E R, Stewart, L, Mather, S, Bates, D O, Harper, S J
• Format: Article
• Language: English
• Subjects: Amino acids; Angiogenesis; Biomedical and Life Sciences; Biomedicine; Cancer Research; Drug Resistance; Epidemiology; Laboratories; Medical research; Molecular Diagnostics; Molecular Medicine; Oncology; Vascular endothelial growth factor
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6605249

Background: The key mediator of new vessel formation in cancer and other diseases is VEGF-A. VEGF-A exists as alternatively spliced isoforms - the pro-angiogenic VEGF xxx family generated by exon 8 proximal splicing, and a sister family, termed VEGF xxx b, exemplified by VEGF 165 b, generated by distal splicing of exon 8. However, it is unknown whether this anti-angiogenic property of VEGF 165 b is a general property of the VEGF xxx b family of isoforms. Methods: The mRNA and protein expression of VEGF 121 b was studied in human tissue. The effect of VEGF 121 b was analysed by saturation binding to VEGF receptors, endothelial migration, apoptosis, xenograft tumour growth, pre-retinal neovascularisation and imaging of biodistribution in tumour-bearing mice with radioactive VEGF 121 b. Results: The existence of VEGF 121 b was confirmed in normal human tissues. VEGF 121 b binds both VEGF receptors with similar affinity as other VEGF isoforms, but inhibits endothelial cell migration and is cytoprotective to endothelial cells through VEGFR-2 activation. Administration of VEGF 121 b normalised retinal vasculature by reducing both angiogenesis and ischaemia. VEGF 121 b reduced the growth of xenografted human colon tumours in association with reduced microvascular density, and an intravenous bolus of VEGF 121 b is taken up into colon tumour xenografts. Conclusion: Here we identify a second member of the family, VEGF 121 b, with similar properties to those of VEGF 165 b, and underline the importance of the six amino acids of exon 8b in the anti-angiogenic activity of the VEGF xxx b isoforms.