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Andrew Dodson, Bertil E. Damato, Sarah E. Coupland, Helen Kalirai; VEGFxxxb Protein Expression Is Downregulated In Monosomy 3 Uveal Melanoma. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3394.
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Metastatic spread of uveal melanoma (UM) occurs hematogenously and almost exclusively in patients whose tumor shows loss of one copy of chromosome 3 (M3). Tumor growth and metastasis requires angiogenesis, which is mediated by factors such as Vascular Endothelial Growth Factor-A (VEGFA). Expression of this factor is linked to metastatic potential of UM. Both pro-angiogenic and anti-angiogenic VEGF variants exist. In other tumor types, downregulation of VEGFxxxb, an alternatively-spliced anti-angiogenic VEGFA isoform, correlates with increased tumor aggressiveness. This is because VEGFxxxb inhibits VEGFR2, a major signaling receptor. Our aims were to determine pro- and anti-angiogenic VEGFA protein levels in UM and correlate these with clinical and histological features.
We examined 50 UM specimens from consenting patients treated by enucleation or local resection between 2007-11. The patients (23 F, 27 M) had a mean age of 59 years (range 24-93). Tumors had a mean largest basal diameter of 15.6mm (range 8-22) with: M3 in 28; closed-loops in 28; epithelioid cells in 27; averaging 7.1 mitoses per 40-HPFs (range 1-21). Immunohistochemical staining was done with the following antibodies: panVEGF and VEGFxxxb; CD68 and CD163 (assessing tumour-associated macrophages (TAMs); and CD34 (assessing tumor vasculature). Percentage of tumor cells staining with each antibody was categorised as: 0 (0%); 1 (1-10%); 2 (11-50%); 3 (51-90%) or 4 (>90%). Staining intensity was categorised as: 0 (negative); 1 (weak); 2 (moderate); 3 (strong). The two categories were added together to give a scoring index (SI). All data were tested in SPSS.
Positive staining for panVEGF and VEGFxxxb was observed in both tumor cells (TC) and infiltrating macrophages (IM). Neither panVEGF nor VEGFxxxb SI in the TC or the IM correlated significantly with largest basal tumor diameter, mitotic count, number of TAM, presence of closed loops, cell type or microvascular density. The panVEGF SI in the TC and IM and VEGFxxxb SI in the IM showed no significant correlation with the UM chromosome 3 status. The VEGFxxxb SI in the TC was significantly lower in M3 UM than in disomy 3 UMs (Spearman’s, p<0.001).
VEGFxxxb expression was reduced in the TC of M3-UM. Diminished angiogenic inhibition may contribute to the growth and metastasis of UMs.
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