Inhibition of MMP-2 and MMP-9 decreases cellular migration, and angiogenesis in in vitro models of retinoblastoma

Retinoblastoma (Rb) is the most common primary intraocular tumor in children. Local treatment of the intraocular disease is usually effective if diagnosed early; however advanced Rb can metastasize through routes that involve invasion of the choroid, sclera and optic nerve or more broadly via the oc...

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Published in:	BMC cancer Vol. 17; no. 1; pp. 434 - 11
Main Authors:	Webb, Anderson H, Gao, Bradley T, Goldsmith, Zachary K, Irvine, Andrew S, Saleh, Nabil, Lee, Ryan P, Lendermon, Justin B, Bheemreddy, Rajini, Zhang, Qiuhua, Brennan, Rachel C, Johnson, Dianna, Steinle, Jena J, Wilson, Matthew W, Morales-Tirado, Vanessa M
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 20-06-2017 BioMed Central BMC
Subjects:	Analysis Angiogenesis Biotechnology Boyden chamber Cancer Cancer metastasis Care and treatment Cell cycle Cell division Cell Line, Tumor Cell Movement - drug effects Cell Survival - drug effects Children Clinical trials Cytokines Development and progression Enzyme-linked immunosorbent assay Extracellular matrix Gelatinase A Gelatinase B Gene expression Genetic aspects Humans Immunomodulation Matrix Metalloproteinase 2 - genetics Matrix Metalloproteinase 9 - genetics Matrix Metalloproteinase Inhibitors - administration & dosage Matrix metalloproteinases Metalloenzymes Metastases Metastasis MMP-2 MMP-9 Mutation Neovascularization, Pathologic - drug therapy Neovascularization, Pathologic - genetics Neovascularization, Pathologic - pathology Optic nerve Physiological aspects Retina Retinoblastoma Retinoblastoma - drug therapy Retinoblastoma - genetics Retinoblastoma - pathology Therapy Transforming growth factor-b1 Tumors Vascular endothelial growth factor Vascular Endothelial Growth Factor A - genetics Wound healing United States Therapy Matrix metalloproteinases MMP-2 VEGF TGF-β1 Metastasis Retinoblastoma MMP-9
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Summary:	Retinoblastoma (Rb) is the most common primary intraocular tumor in children. Local treatment of the intraocular disease is usually effective if diagnosed early; however advanced Rb can metastasize through routes that involve invasion of the choroid, sclera and optic nerve or more broadly via the ocular vasculature. Metastatic Rb patients have very high mortality rates. While current therapy for Rb is directed toward blocking tumor cell division and tumor growth, there are no specific treatments targeted to block Rb metastasis. Two such targets are matrix metalloproteinases-2 and -9 (MMP-2, -9), which degrade extracellular matrix as a prerequisite for cellular invasion and have been shown to be involved in other types of cancer metastasis. Cancer Clinical Trials with an anti-MMP-9 therapeutic antibody were recently initiated, prompting us to investigate the role of MMP-2, -9 in Rb metastasis. We compare MMP-2, -9 activity in two well-studied Rb cell lines: Y79, which exhibits high metastatic potential and Weri-1, which has low metastatic potential. The effects of inhibitors of MMP-2 (ARP100) and MMP-9 (AG-L-66085) on migration, angiogenesis, and production of immunomodulatory cytokines were determined in both cell lines using qPCR, and ELISA. Cellular migration and potential for invasion were evaluated by the classic wound-healing assay and a Boyden Chamber assay. Our results showed that both inhibitors had differential effects on the two cell lines, significantly reducing migration in the metastatic Y79 cell line and greatly affecting the viability of Weri-1 cells. The MMP-9 inhibitor (MMP9I) AG-L-66085, diminished the Y79 angiogenic response. In Weri-1 cells, VEGF was significantly reduced and cell viability was decreased by both MMP-2 and MMP-9 inhibitors. Furthermore, inhibition of MMP-2 significantly reduced secretion of TGF-β1 in both Rb models. Collectively, our data indicates MMP-2 and MMP-9 drive metastatic pathways, including migration, viability and secretion of angiogenic factors in Rb cells. These two subtypes of matrix metalloproteinases represent new potential candidates for targeted anti-metastatic therapy for Rb.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1471-2407 1471-2407
DOI:	10.1186/s12885-017-3418-y