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MR Ritter, MI Dorrell, S Friedlander, T Vecchione, R Holmes, S Cohen, M Friedlander; IGF2 and Potential Regulators of Periorbital Hemangioma Progression Identified by Large-Scale Expression Analysis . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3708.
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Purpose: Hemangiomas are benign tumors of the vascular endothelium. These tumors frequently occur periorbitally and follow a unique course with an initial phase of rapid proliferation followed by a plateau phase and, in most cases, spontaneous involution. These characteristics provide an opportunity to investigate the changes in gene expression that may be responsible for regulating the growth and regression of vascular tumors and, in addition, may provide insight into general mechanisms regulating angiogenesis that can be expanded to include ocular neovascular diseases. Methods: DNA microarrays representing approximately 10,000 human genes were used with quantitative RT-PCR to confirm results. Immunohistochemistry was used to determine the quantity and localization of protein. A hemangioma model was employed by embedding freshly resected hemangioma tissue into fibrin gels. Results: We demonstrate that hemangiomas express high levels of insulin-like growth factor 2 (IGF2) mRNA and protein during the proliferative phase with substantial decrease in expression during involution. Changes in IGF2 expression were confirmed by quantitative RT-PCR. IGF2 protein was found to localize primarily to tumor vessels of proliferating lesions. On the functional level, IGF2 protein was shown to promote the growth of microvessels from cultured human hemangioma explants. Genes related to angiogenesis and proliferating endothelial cells were also expressed during proliferation including integrins alphavbeta3 and alpha5beta1. During the involuting phase, microarray analysis demonstrated increases in expression of a number of interferon-induced genes. Conclusion: These studies identify novel potential regulators of periorbital hemangioma growth and involution and provide a foundation on which to build further mechanistic investigations into angiogenesis using hemangiomas as a model.
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