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Phosphorylated pVEGFR2/KDR receptor expression in uveal melanomas: relation with HIF2α and survival

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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.

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Authors and Affiliations

  1. Department of Pathology, Democritus University of Thrace Medical School, and University General Hospital of Alexandroupolis, P.O. Box 12, 68100, Alexandroupolis, Greece

    Alexandra Giatromanolaki & Efthimios Sivridis

  2. Department of Ophthalmology, University of Innsbruck Medical School, Innsbruck, Austria

    Nikolaos E. Bechrakis

  3. Department of Ophthalmology, Charité Medical University, Campus Benjamin Franklin, Berlin, Germany

    Gregor Willerding, Georgios St. Charitoudis & Michael H. Foerster

  4. Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine and Nuffield Department of Clinical Laboratory Science, University of Oxford and John Radcliffe Hospital, Oxford, OX3 7LJ, UK

    Kevin C. Gatter & Adrian L. Harris

  5. Department of Radiotherapy/Oncology, Democritus University of Thrace Medical School, Alexandroupolis, Greece

    Michael I. Koukourakis

Authors
  1. Alexandra Giatromanolaki
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  2. Efthimios Sivridis
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  3. Nikolaos E. Bechrakis
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  4. Gregor Willerding
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  5. Georgios St. Charitoudis
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  6. Michael H. Foerster
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  7. Kevin C. Gatter
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  8. Adrian L. Harris
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  9. Michael I. Koukourakis
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Correspondence to Alexandra Giatromanolaki.

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Giatromanolaki, A., Sivridis, E., Bechrakis, N.E. et al. Phosphorylated pVEGFR2/KDR receptor expression in uveal melanomas: relation with HIF2α and survival. Clin Exp Metastasis 29, 11–17 (2012). https://doi.org/10.1007/s10585-011-9424-6

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  • DOI: https://doi.org/10.1007/s10585-011-9424-6

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