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C.-C. Chan, C. Yin, X. Ding, D. Shen, M. Patel, Z. Zhuang; Murine Model of Von Hippel-Lindau (VHL) Associated Ocular Hemangioblastoma. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5684.
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von Hippel-Lindau Disease (VHL) is an autosomal dominant inherited systemic cancer syndrome. Sixty percent of patients with VHL possess retinal hemangioblastomas (RH) that often present bilaterally and can lead to blindness. RH are composed of large foamy stromal (tumor) cells admixed with many prominent capillary channels lined with endothelial or endothelial-like cells. High expression of VEGF, low clusterin, and co-expression of Epo and EpoR are characteristic of RH. Currently neither an animal model nor a cure for ocular VHL exists. We report a new model for this lesion.
Human UMRC-6 cells (104 cells/1µl), a VHL- associated renal clear cell carcinoma cell line, were injected into adult SKID mice either peritoneally (200µl/mouse) or intravitreally (2µl/eye). Mice were monitored clinically and under fundoscopic examination weekly. Mice were euthanized on weeks 2, 3 or 4 post inoculation, and eyes and brains were processed for histology. Immunohistochmistry was performed for CD31, CD34, collage IV, CD133, VEGF, clusterin, Epo and EpoR with avidin-biotin complex immunoperoxidase. Real-time RT-PCR was conducted to measure VEGF, clusterin, Epo and EpoR in ocular tumor cells with TaqMan.
Three independent experiments demonstrated that mice subjected to intravitreal inoculation of UMRC-6 cells develop an ocular RH-like VHL tumor characterized by a thin layer of tumor cells adherent to posterior lens capsule in the vitreous. Few small cysts resembling fine vascular -like channels were noted among tumor cells. No tumor cells were found in the eyes and brains of mice with intraperitoneal injection. Co-expression of Epo and EpoR was found in the tumor cells at both the protein and transcript levels. Tumor cells also exhibited a significantly decreased clusterin mRNA and minimally increased VEGF mRNA. Tumors were weakly positive for CD31 and CD34. Interestingly, VEGF transcript markedly increased in the mice retina.
Intravitreal injection of UMRC-6 cells is a novel model for ocular VHL-associated tumor that posses angiogenesis potential. This model may be utilized to further elucidate the molecular and cellular mechanisms of ocular VHL diseases.
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