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Anderson Hudgens Webb, Nabil Saleh, Bradley T Gao, Ryan P Lee, Justin B Lendermon, Matthew W Wilson, Vanessa Marie Morales; The Effects of Modulation of MMP-2 and MMP-9 in Angiogenesis and Invasive Potential in Retinoblastoma. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):67.
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© ARVO (1962-2015); The Authors (2016-present)
Retinoblastoma (Rb) is the most common primary intraocular tumor in children. Effective local treatment exists, but occasionally Rb can metastasize. Metastases are attributed to extra-retina invasion of the ocular coats and the optic nerve. In this study we investigate modulation of Matrix Metalloproteinases (MMP), responsible for degradation of the extracellular matrix and invasion, as a potential adjuvant therapeutic target for Rb.
Three different Rb cell lines, Rb-Y79, Rb-Weri and Rb-355, were analyzed by gene expression, protein levels, and secretion of MMP-2 and MMP-9 by RT-PCR, Zymmography, and ELISA. Flow cytometry examined the levels of ICAM, VEGF, and CD31 as surrogates of adhesion, invasion, and angiogenesis. We evaluated the effect of pharmacological inhibition of MMP-2 (ARP100, Santa Cruz Biotechnology, Dallas, TX) and MMP-9 (AG-L-66085, Santa Cruz Biotechnology) by magnetic levitation (Nano3D Biosciences, Inc, Houston, TX) to determine their effects on angiogenesis and invasion.
Our results show the three different Rb cell lines express different levels of MMP-2 and MMP-9 mRNA. MMP-9 expression increased upon cell activation by using Phorbol 12-myristate 13-acetate (PMA) and was reduced upon use of the MMP-2 and -9 inhibitors. Magnetic levitation analysis showed reduction in Rb tumor masses in vitro by pharmacological inhibition of MMP-2 and MMP-9.
Inhibition of MMP-2 and MMP-9, both markers of invasion, decreased expression of CD31 and VEGF, both markers of angiogenesis. MMP2 and MMP9 are potential candidates for targeted therapy.
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