Abstract
Matrix metalloproteinases (MMPs) are endopeptidases that play pivotal roles in promoting tumor disease progression, including tumor angiogenesis. In many solid tumors, MMP expression could be attributed to tumor stromal cells and is partially regulated by tumor-stroma interactions via tumor cell-associated extracellular matrix metalloproteinase inducer (EMMPRIN). The role of EMMPRIN during tumor angiogenesis and growth was explored by modulating EMMPRIN expression and activity using recombinant DNA engineering and neutralizing antibodies. In human breast cancer cells, changes in EMMPRIN expression influenced vascular endothelial growth factor (VEGF) production at both RNA and protein levels. In coculture of tumor cells and fibroblasts mimicking tumor-stroma interactions, VEGF expression was induced in an EMMPRIN- and MMP-dependent fashion, and was further enhanced by overexpressing EMMPRIN. Conversely, VEGF expression was inhibited by suppressing EMMPRIN expression in tumor cells, by neutralizing EMMPRIN activity, or by inhibiting MMPs. In vivo, EMMPRIN overexpression stimulated tumor angiogenesis and growth; both were significantly inhibited by antisense suppression of EMMPRIN. Expression of both human and mouse VEGF and MMP, derived from tumor and host cells, respectively, was regulated by EMMPRIN. These results suggest a novel tumor angiogenesis mechanism in which tumor-associated EMMPRIN functionally mediates tumor-stroma interactions and directly contributes to tumor angiogenesis and growth by stimulating VEGF and MMP expression.
Highlights
Tumor angiogenesis is a complex and multistep process [1]
In coculture of tumor cells with fibroblasts, matrix metalloproteinases (MMPs)-2 and MMP-9 production was regulated in an EMMPRINdependent fashion (Fig. 1)
Since tumor cell–associated extracellular matrix metalloproteinase inducer (EMMPRIN) is believed to be a critical mediator of the interactions between tumor cells and surrounding stromal fibroblasts, we studied whether EMMPRIN expression influenced vascular endothelial growth factor (VEGF) production in the coculture of tumor cells and fibroblasts
Summary
Tumor angiogenesis is a complex and multistep process [1]. Critical steps during tumor angiogenesis are the outgrowth of endothelial cells from preexisting capillary vessels initiated by the migration of endothelial cells away from the parental vessels. After the dissociation of these endothelial cells can they proliferate in response to various angiogenic growth factors, including vascular endothelial growth factor (VEGF). Proliferating endothelial cells subsequently remodel the extracellular matrix around neovasculature sites, align into tube-like structures, and eventually. Extracellular matrix remodeling occurs continuously throughout the tumor angiogenic process in a well-orchestrated fashion involving numerous extracellular matrix– degrading enzymes. Matrix metalloproteinases (MMPs) are believed to be a critical group of enzymes that affect tumor angiogenesis, tumor growth, local invasion, and subsequent distant metastasis [2, 3]. MMPs are a family of metal-dependent endopeptidases sharing a common modular domain structure, which are capable of cleaving all of the extracellular matrix components of the parenchymal and vascular basement membranes, normally mechanical barriers to cell migration and invasion. MMP activity has been directly associated with tumor angiogenic potential [4, 5]
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