title: Phosphorylated pVEGFR2/KDR receptor expression in uveal melanomas: relation with HIF2α and survival.
abstract: Hypoxia and its down-stream activated pathways are commonly involved in tumor progression. Genes involved in angiogenesis and glycolysis, i.e. vascular endothelial growth factor (VEGF) and lactase dehydrogenase A (LDHA), respectively, are transcriptionally controlled by the hypoxia inducible factors 1α and 2α (HIF1α and HIF2α). A series of 60 uveal melanomas were immunohistochemically assessed for the expression of VEGF and the phosphorylated/activated form of VEGF receptor 2 (pVEGFR2/KDR), after binding to VEGF. The expression of HIF1α, HIF2α and LDH5 was also investigated. Uveal melanomas overexpressing HIF2α (but not that of HIF1α) were significantly associated with high VEGF (P = 0.005), pVEGFR2/KDR (P < 0.0001) and LDH5 (P ≤ 0.0001). High LDH5 was linked with tumor necrosis (P = 0.01) and increased tumor size (P = 0.03). High VEGF was linked with phosphorylated pVEGFR2/KDR receptors. In univariate analysis high pVEGFR2/KDR receptor expression was significantly related with poor prognosis (P = 0.02). It is concluded that HIF2α plays an important role in the progression of uveal melanomas possibly by promoting the autocrine loop VEGF-pVEGFR2/KDR, and by enhancing the expression of LDHA gene, conferring thus a growth advantage. As pVEGFR2/KDR expression was significantly related with poor prognosis, inhibitors of this receptor may improve the clinical outcome of patients with pVEGFR2/KDR overexpressing uveal melanomas.
authors: Department of Pathology, Democritus University of Thrace Medical School, and University General Hospital of Alexandroupolis, P.O. Box 12, 68100, Alexandroupolis, Greece. agiatrom@med.duth.gr
authors: Alexandra
authors: A
authors: Giatromanolaki
authors: Efthimios
authors: E
authors: Sivridis
authors: Nikolaos E
authors: NE
authors: Bechrakis
authors: Gregor
authors: G
authors: Willerding
authors: Georgios
authors: G
authors: St Charitoudis
authors: Michael H
authors: MH
authors: Foerster
authors: Kevin C
authors: KC
authors: Gatter
authors: Adrian L
authors: AL
authors: Harris
authors: Michael I
authors: MI
authors: Koukourakis
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008545:Melanoma / Q000378:metabolism*; D010766:Phosphorylation; D016019:Survival Analysis; D014604:Uveal Neoplasms / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099162:Endothelial PAS Domain-Containing Protein 1