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Balance of pro‐ versus anti‐angiogenic splice isoforms of vascular endothelial growth factor as a regulator of neuroblastoma growth
Author(s) -
PeirisPagès Maria,
Harper Steven J,
Bates David O,
Ramani Pramila
Publication year - 2010
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2746
Subject(s) - angiogenesis , gene isoform , vascular endothelial growth factor , biology , cancer research , neuroblastoma , vascular endothelial growth factor a , alternative splicing , medicine , endocrinology , cell culture , microbiology and biotechnology , vegf receptors , gene , biochemistry , genetics
Neuroblastoma (NB) is the second most common extracranial tumour of childhood. Angiogenesis plays a crucial role in the growth and development of NB and vascular endothelial growth factor (VEGF), one of the most potent stimuli of angiogenesis, has been studied extensively in vitro . VEGF 165 has been shown to be the predominant angiogenic isoform expressed in NB cell lines and tumours. In this study, we investigated the anti‐angiogenic isoform of VEGF‐A, generated from distal splice site selection in the terminal exon of VEGF (VEGF 165 b) and shown to be down‐regulated in epithelial malignancies. The expression of both the pro‐ (VEGF xxx ) and the anti‐angiogenic (VEGF xxx b) isoforms was compared in a range of NB and ganglioneuroma (GN) tumours. Whereas VEGF xxx b and VEGF xxx were both expressed in GN, specific up‐regulation of the VEGF xxx isoforms was seen in NB at RNA and protein levels. Highly tumourigenic NB cell lines also showed up‐regulation of the angiogenic isoforms relative to VEGF xxx b compared to less tumourigenic cell lines, and the isoforms were differentially secreted. These results indicate that VEGF 165 is up‐regulated in NB and that there is a difference in the balance of isoform expression from anti‐angiogenic VEGF 165 b to angiogenic VEGF 165 . Treatment with recombinant human VEGF 165 b significantly reduced the growth rate of established xenografts of SK‐N‐BE(2)‐C cells (4.24 ± 1.01 fold increase in volume) compared with those treated with saline (9.76 ± 3.58, p < 0.01). Microvascular density (MVD) was significantly decreased in rhVEGF 165 b‐treated tumours (19.4 ± 1.9 vessels/mm 3 ) in contrast to the saline‐treated tumours (45.5 ± 8.6 vessels/mm 3 ). VEGF 165 b had no significant effect on the proliferative or apoptotic activity, viability or cytotoxicity of SK‐N‐BE(2)‐C cells after 48 h. In conclusion, VEGF 165 b is an effective inhibitor of NB growth. These findings provide the rationale for further investigation of VEGF 165 b in NB and other paediatric malignancies. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.