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Stanley Park, Yujuan Wang, Kristin Huntoon, DeFen Shen, Zhengping Zhuang, Chi-Chao Chan; Using a Murine Xenograft Model for Von Hippel-Lindau Disease-Associated Retinal Hemangioblastomas to Test Novel Therapies. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5882.
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Von Hippel-Lindau (VHL) disease is an autosomal dominant multisystemic disorder that gives rise to cystic and/or highly vascularized tumors. VHL is mutated or deleted and makes non-functional VHL protein leading to constitutive expression of hypoxia-inducible factor (HIF). This causes high levels of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and erythropoietin (EPO) to be expressed in the tumor cell. Patients commonly present with retinal hemangioblastomas (RH) which can cause severe visual morbidity. VHL-null animal models do not fully recapitulate common features of human VHL disease and leave us with a limited understanding on targeted therapies for RH. Here we designed a murine xenograft model to evaluate new treatments for VHL disease-associated RH.
We used severe combined immunodeficiency (SCID) mice and intravitreally inoculated them with UMRC6 cells, a human VHL-null renal cell carcinoma cell line. The mice were either given an EPO receptor antagonist or a dual VEGF and PDGF kinase receptor antagonist. Treatment efficacy was evaluated by clinical fundoscopy. Eyes showing progressive obscuration of the retinal vasculature and optic nerve head from baseline were given +1 score. Those that showed clinical improvement were given -1, those that had no change were given 0.
At least two experiments were performed with two different agents and the data were repeatable. By clinical scoring of the fundus photographs, mice treated with the dual receptor inhibitor (n= 13) showed no significant improvements when compared to those given vehicle solution (n= 13). No treated mice demonstrated clinical improvement while 53.8% (7/13) worsened. On the other hand, mice treated with the EPO receptor antagonist (n= 16) demonstrated modest clinical improvement when compared to mice given PBS (n= 17, p<0.01). 31.3% (5/16) improved while only 12.5% (2/16) worsened. On histology, layers of UMRC6 cells with cysts and fine vascular-like structures formed behind the posterior capsule of the lens. Scattered inflammatory cells were also admixed with UMRC6 cells in some areas. There was no significant improvement in any treated mice on histology.
This model may be a useful tool for testing therapeutic agents. EPO receptor antagonism appears to be a promising therapeutic option for treating this model.
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