TY - JOUR
T1 - Hypoxia-inducible factor 1 upregulation of both VEGF and ANGPTL4 is required to promote the angiogenic phenotype in uveal melanoma
AU - Hu, Ke
AU - Babapoor-Farrokhran, Savalan
AU - Rodrigues, Murilo
AU - Deshpande, Monika
AU - Puchner, Brooks
AU - Kashiwabuchi, Fabiana
AU - Hassan, Syed Junaid
AU - Asnaghi, Laura
AU - Handa, James T.
AU - Merbs, Shannath
AU - Eberhart, Charles G.
AU - Semenza, Gregg L.
AU - Montaner, Silvia
AU - Sodhi, Akrit
N1 - Funding Information:
Dr. Sodhi gratefully acknowledges the support he receives as a Special Scholar Award recipient from the Research to Prevent Blindness Foundation. Dr. Handa is the Robert Bond Welch Professor.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Angiogenesis
KW - Angiopoietin-like 4 (ANGPTL4)
KW - Choroidal melanoma
KW - Hypoxia inducible factor-1α
KW - Vascular endothelial growth factor (VEGF)
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U2 - 10.18632/oncotarget.6868
DO - 10.18632/oncotarget.6868
M3 - Article
C2 - 26761211
AN - SCOPUS:84958817661
SN - 1949-2553
VL - 7
SP - 7816
EP - 7828
JO - Oncotarget
JF - Oncotarget
IS - 7
ER -