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Nabil Saleh, Anderson Hudgens Webb, Bradley T Gao, Ryan P Lee, Justin B Lendermon, Matthew W Wilson, Vanessa Marie Morales; Modulation of MMP-2 and MMP-9 as Potential Adjuvant Therapy to Limit the Growth of Metastatic Uveal Melanoma. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5338.
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© ARVO (1962-2015); The Authors (2016-present)
Our study focused on the progression and invasion of uveal melanoma (UM), the most common intraocular malignancy in adults. Degradation of the extracellular matrix is a critical step during tumor progression as it correlates with the ability of the microenvironment to restrict tumor growth. Matrix metalloproteinases (MMPs) are a family of zinc ion-dependent endopeptidases, which digest different substrates present in the tissue. Regulation of MMPs during the interplay of the tumor and the surrounding microenvironment is still unclear.
We cultured three lines of UM cells (Mel 270, OMM1, and 92.1). Each cell lines were exposed to the common phorbol esters Phorbol 12-myristate 13-acetate (PMA) and 12-O-Tetradecanoylphorbol-13-Acetate (TPA) at varying concentrations, and to pharmacological inhibitors of MMP-2 and MMP-9 (ARP100 and AG-L-66085, Santa Cruz Biotechnology, Dallas, TX). Genomic studies and protein analyses were conducted to determine the expression of MMP-2 and MMP-9. To study effect of drug on tumor (spheroid) size, Nano3D BioPrinting assays (Nano3D Biosciences, Inc, Houston, TX) were performed.
Our results show MMP-2 and MMP-9 mRNA expression in UM cell lines. The expression levels are higher in the metastatic UM cell line OMM1. Gene expression was reduced upon use of inhibitors, even when phorbol esters were used. Tumor shrinkage was observed when MMP-9 inhibitors were used in the metastatic UM cell line as measured by the Nano3D BioPrinting assay.
In this study, we investigated the changes in uveal melanoma progression in vitro after pharmacological inhibition of MMP-2 and MMP-9. Both inhibitors reduced expression of the expected targeted genes, however only the MMP-9 slowed the reduction in spheroid size. Our studies revealed pharmacological inhibition of MMP-9 reduced the size of the tumor spheroids of metastatic UM cell line in vitro.
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