VEGF165b, an Inhibitory Vascular Endothelial Growth Factor Splice Variant

Woolard, Jeanette; Wang, Wenying; Bevan, Heather S.; Qiu, Yan; Morbidelli, Lucia; Pritchard-Jones, Rowan; Cui, Tai-Gen; Sugiono, Marto; Waine, Elizabeth; Perrin, Rachel M.; Foster, Rebecca R.; Digby-Bell, Jonathan; Shields, Jacqueline D.; Whittles, CE; Mushens, Rosey; Gillatt, David; Ziche, Marina; Harper, Steven J.; Bates, David O.

doi:10.1158/0008-5472.can-04-0934

Cited by 390 publications

(300 citation statements)

References 59 publications

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“…The antibody used here is an affinity-purified monoclonal antibody, and has been shown using Western blotting (Woolard et al, 2004;Perrin et al, 2005), immunohistochemistry (Woolard et al, 2004) and ELISA (Woolard et al, 2004;Bates et al, 2006) even when present at 10 000-fold greater concentrations (Perrin et al, 2005). The downregulation of the VEGF xxx b isoforms identified here, if confirmed in a larger study, would greatly simplify the procedure for identifying patients at risk.…”

Section: Discussionmentioning

confidence: 73%

“…MAB3045). It has previously been shown to have specificity for the VEGF 165 b isoform over the VEGF 165 isoforms, and does not detect VEGF 165 , or VEGF 121 , recombinant protein (Woolard et al, 2004;Perrin et al, 2005). It does detect proteins consistent with VEGF xxx b isoforms such as VEGF 121 b, VEGF 165 b, VEGF 145 b and VEGF 189 b in human tissues.…”

Section: Vegf XXX B Immunohistochemistrymentioning

confidence: 99%

“…This antibody has previously been shown to detect both VEGF xxx b and VEGF xxx isoforms, and both heparin-binding and nonheparin-binding isoforms (Woolard et al, 2004;Perrin et al, 2005). Serial sections (6 mm) were cut from tissue blocks of excised melanoma from the melanoma archive at Frenchay Hospital, Bristol.…”

Section: -Test)mentioning

confidence: 99%

“…The mRNA encoding this isoform, termed VEGF 165 b (Bates et al, 2002; Figure 1), was demonstrated in renal cortical tissue, and almost all other normal tissues examined. Subsequent work has identified other isoforms using this distal splice site (DSS), including VEGF 121 b, VEGF 189 b and VEGF 145 b in normal human tissues (Woolard et al, 2004;Perrin et al, 2005). This alternative family of isoforms is termed the VEGF xxx b family, in contrast with the VEGF xxx family where xxx denotes the aminoacid number (Perrin et al, 2005).…”

mentioning

confidence: 99%

“…Expression of VEGF 165 b mRNA was downregulated in renal cell carcinoma (Bates et al, 2002), prostate cancer (Woolard et al, 2004) and the vitreous of patients with diabetic retinopathy (Perrin et al, 2005), all angiogenic conditions. Subsequently, VEGF 165 b protein was shown to significantly and dose dependently inhibit VEGF 165 -mediated proliferation and migration of endothelial cells, vasodilatation of mesenteric arteries and angiogenesis in two different models of VEGF 165 -driven blood vessel growth (Woolard et al, 2004). Furthermore, it has been shown to inhibit hypoxia-driven angiogenesis in the retina (Konopatskaya et al, 2006).…”

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confidence: 99%

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Expression of VEGFxxxb, the inhibitory isoforms of VEGF, in malignant melanoma

et al. 2007

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Malignant melanoma is the most lethal of the skin cancers and the UK incidence is rising faster than that of any other cancer. Angiogenesis -the growth of new vessels from preexisting vasculature -is an absolute requirement for tumour survival and progression beyond a few hundred microns in diameter. We previously described a class of anti-angiogenic isoforms of VEGF, VEGF xxx b, that inhibit tumour growth in animal models, and are downregulated in some cancers, but have not been investigated in melanoma. To determine whether VEGF xxx b expression was altered in melanoma, PCR and immunohistochemistry of archived human tumour samples were used. In normal epidermis and in a proportion of melanoma samples, VEGF xxx b staining was seen. Some melanomas had much weaker staining. Subsequent examination revealed that expression was significantly reduced in primary melanoma samples (both horizontal and vertical growth phases) from patients who subsequently developed tumour metastasis compared with those who did not (analysis of variance (ANOVA) Po0.001 metastatic vs nonmetastatic), irrespective of tumour thickness, while the surrounding epidermis showed no difference in expression. Staining for total VEGF expression showed staining in metastatic and nonmetastatic melanomas, and normal epidermis. An absence of VEGF xxx b expression appears to predict metastatic spread in patients with primary melanoma. These results suggest that there is a switch in splicing as part of the metastatic process, from anti-angiogenic to pro-angiogenic VEGF isoforms. This may form part of a wider metastatic splicing phenotype.

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Section: Discussionmentioning

confidence: 73%

Section: Vegf XXX B Immunohistochemistrymentioning

confidence: 99%

Section: -Test)mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Expression of VEGFxxxb, the inhibitory isoforms of VEGF, in malignant melanoma

et al. 2007

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Comparing Pegaptanib and Triamcinolone Efficacy in the Rat Choroidal Neovascularization Model

Criswell

Hu²,

Steffens³

et al. 2008

Arch Ophthalmol

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To evaluate the prophylactic effect of intravitreal pegaptanib sodium on choroidal neovascularization membrane (CNVM) development and compare its performance with that of triamcinolone acetonide. Methods: In drug-treated and control groups, CNVMs were induced by laser trauma. Immediately after undergoing the laser procedure, animals received intravitreal injections of pegaptanib sodium, 8 or 17 µg; triamcinolone acetonide, 200 µg; or a vehicle solution. After 21 days, fluorescein angiography was performed. The CNVM mean diameters and radial thicknesses were measured histologically. Results: Mean CNVM diameters were 10% to 13% smaller in pegaptanib-treated eyes and 43% smaller in triamcinolone-treated eyes compared with laser-only control eyes. Late-stage fluorescein angiography leakage scores, on a scale of 0 to 3, suggested a statistical difference between triamcinolone-(0.6) and pegaptanib 8 µg-treated (1.5) groups compared with the laser-only control group (2.0). The CNVM mean thicknesses were greater in the pegaptanib 8 µg-(79 µm) and pegaptanib 17 µg-treated (71 µm) groups and significantly smaller in the triamcinolonetreated group (26 µm) compared with the laser-only control group (67 µm). Conclusion: In this animal model of choroidal neovascularization, intravitreal pegaptanib exhibited marginal or no effect on CNVM development; whereas intravitreal triamcinolone evoked robust inhibition of CNVMs. Clinical Relevance: Pegaptanib treatment may be insufficient to prevent CNVM formation.

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Receptor Tyrosine Kinases

Matthews¹,

Gerritsen²

2010

Targeting Protein Kinases for Cancer Therapy

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VEGF165b, an Inhibitory Vascular Endothelial Growth Factor Splice Variant

Cited by 390 publications

References 59 publications

Expression of VEGFxxxb, the inhibitory isoforms of VEGF, in malignant melanoma

Expression of VEGFxxxb, the inhibitory isoforms of VEGF, in malignant melanoma

Comparing Pegaptanib and Triamcinolone Efficacy in the Rat Choroidal Neovascularization Model

Receptor Tyrosine Kinases

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