Hypoxia-inducible factor 1 upregulation of both VEGF and ANGPTL4 is required to promote the angiogenic phenotype in uveal melanoma
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Ke Hu1,2,*, Savalan Babapoor-Farrokhran1,*, Murilo Rodrigues1, Monika Deshpande1, Brooks Puchner1, Fabiana Kashiwabuchi1, Syed Junaid Hassan1, Laura Asnaghi3, James T. Handa1, Shannath Merbs1, Charles G. Eberhart1,3, Gregg L. Semenza4, Silvia Montaner5 and Akrit Sodhi1
1 Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA
2 The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
3 Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
4 Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, Biological Chemistry, and Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
5 Department of Oncology and Diagnostic Sciences, Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA
* These authors have contributed equally to this work
Akrit Sodhi, email:
Keywords: choroidal melanoma, angiogenesis, angiopoietin-like 4 (ANGPTL4), vascular endothelial growth factor (VEGF), hypoxia inducible factor-1α
Received: September 03, 2015 Accepted: January 04, 2016 Published: January 09, 2016
Purpose: Expression of the hypoxia-inducible factor (HIF)-1-regulated gene product, vascular endothelial growth factor (VEGF), correlates with tumor vascularity in patients with uveal melanoma (UM). While the relationship between HIF-1 and VEGF in cancer is well-studied, their relative contribution to the angiogenic phenotype in UM has not previously been interrogated. Here we evaluate the contribution of HIF-1, VEGF, and a second HIF-1-regulated gene product, angiopoietin-like 4 (ANGPTL4), to angiogenesis in UM.
Experimental Design: UM cells were examined for expression of HIF-1α, VEGF, and ANGPTL4. Their contribution to the angiogenic potential of UM cells was assessed using the endothelial cell tubule formation and directed in vivo angiogenesis assays. These results were corroborated in tissue from UM animal models and in tissue from patients with UM.
Results: Inhibition of VEGF partially reduced tubule formation promoted by conditioned medium from UM cells. Inhibition of ANGPTL4, which was highly expressed in hypoxic UM cells, a UM orthotopic transplant model, a UM tumor array, and vitreous samples from UM patients, inhibited the angiogenic potential of UM cells in vitro and in vivo; this effect was additive to VEGF inhibition.
Conclusions: Targeting both ANGPTL4 and VEGF may be required for the effective inhibition of angiogenesis in UM.
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