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Angiogenesis, Metastasis, and the Cellular Microenvironment

Elevated Membrane-Type Matrix Metalloproteinases in Gliomas Revealed by Profiling Proteases and Inhibitors in Human Cancer Cells¹

¹ School of Biological Sciences, University of East Anglia, Norwich, Norfolk, United Kingdom;
² Departments of Oncology and ³ Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada; and
⁴ Tom Baker Cancer Centre, Alberta, Canada

Requests for reprints: Dylan Edwards, School of Biological Sciences, University of East Anglia, Norwich, Norfolk NR4 7TJ, United Kingdom. Phone: 44-1603-592184; Fax: 44-1603-592250. E-mail: dylan.edwards{at}uea.ac.uk

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) regulate proteolysis of the extracellular matrix and other extracellular proteins, including growth factors and their receptors. The aberrant expression of these genes is common in most cancers. We profiled the RNA levels of every human MMP and TIMP in a variety of cell types (fibroblast, endothelial, hematopoietic, carcinoma, melanoma, and glioma) using quantitative PCR, with the aim of identifying novel expression patterns. Almost all members of the membrane-type (MT-) MMP and TIMP families were elevated in glioma lines compared to carcinomas. In clinical glioma specimens, there were positive correlations between glioma grade and RNA levels of MT-1, MT-2, and MT-6 MMP, TIMP-1 and TIMP-2, and for several growth factors and receptors. These findings suggest that advanced malignant gliomas have elevated levels of membrane-associated MMPs and TIMPs, which may potentially regulate vascularization and invasion. Concurrent elevation of signaling molecules suggests potential bidirectional relationships that enhance tumor aggressiveness.

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