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M.E. Jockovich; Evaluation of Intratumoral Vascular Development and Localization of Angiogenesis Promoting Factors in the LHBETATAG Murine Transgenic Model of Retinoblastoma: A Potential Target for Antiangiogenic Therapy . Invest. Ophthalmol. Vis. Sci. 2004;45(13):3558.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To investigate intratumoral vascular development and to localize angiogenesis promoting factors as a function of age and tumor size in the LHBETATAG transgenic model for retinoblastoma. Methods: Sixty–four eyes obtained from LHBETATAG mice of 4, 8, 10, and 16 weeks of age were analyzed for retinal tumor volume and intratumoral blood vessel development. Group A. Forty tumor containing eyes (10 per group) were stained with haematoxylin & eosin for tumor volume measurement and with PAS for vascular density assessment. Group B. Angiogenesis promoting factors were localized in 24 eyes (6 per age group) by immunohistochemistry using antibodies against urokinase plasminogen activator receptor (uPAR) and vascular endothelial growth factor receptor (VEGFR2). Blood vessels were detected by lectin (griffonia simplicifolia) staining. Results: Group A. Retinal tumor volume in LHBETATAG mice increases as a function of age. As reported, microscopic tumor formation initiates at four weeks of age. At 8 weeks, tumor sizes encompass 5.0 % (±0.4%) of the intravitreal cavity, 13.2 % (±3.6%) at 10 weeks and 72.0 % (± 20.0%) by 16 weeks of age. Gross tumor vasculature increases proportionally to tumor volume (p <0.01). Vascular density remains constant throughout tumor progression. Group B. Angiogenesis promoting factors parallel tumor volume increase in these LHBETATAG eyes. Receptors for urokinase plasminogen activator and vascular endothelial growth factor were absent in 4 week old mouse eyes but localized to areas of vasculature found throughout retinal tumors in 16 week old LHBETATAG mice (p < 0.01). Conclusions: Retinoblastoma tumor volume increases as a function of post–gestational age in the LHBETATAG transgenic murine model. Tumor vasculature increases parallel with retinoblastoma tumor volume and maintains a constant vascular density. Angiogenesis promoting factors are present throughout the retinoblastoma tumor and show a proportional increase that parallels increasing tumor volume. These results offer insight into retinoblastoma tumor vascular development. The understanding of retinoblastoma tumor vascular development may provide new targets for the treatment of pediatric retinoblastoma with an emphasis on antiangiogenic therapy.
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