Distinct expression patterns and levels of enzymatic activity of matrix metalloproteinases and their inhibitors in primary brain tumors

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have b een implicated in the immense invasive potential and neovascularization of primary brain tumors. We investigated the gene expression profiles of MMPs 1, 2. 3. 7. 9. 12. 13. 14. 16 and of TIMPs 1, 2. 3. and 4 in various primar y brain tumors (astrocytoma WHO grade I-III, glioblastoma. PNET. ependymona III and oligoastrocytoma II) using novel RNase protection assay probe jets . In addition, we determined the level and cellular source of gelatinolytic activity and localized gelatinase B and TIMP-1 RNA. Distinct expression pa tterns of the MMP and TIMP genes were found in the various brain tumors res ted. While the WHO grade I and ii tumors had MT1/MT3 ratios below i. the ma lignant (grade III and IV) tumors had ratios above 1. Strong expression of TIMP-1 RNA was observed in all malignant tumors and in grade I pilocytic as trocytomas and localized to the walls of neovessels. Quantitative analysis of enzymatic activity in the soluble fraction of protein extracts revealed that in most tumors gelatinases remained in the inactive pro-form. In situ zymography revealed net gelatinolytic activity in neurons of normal brain a nd in tumor cells and vessel walls of all tumors tested. Immunohistochemist ry demonstrated that gelatinase B was localized to vessel walls. to neutrop hils in areas of hemorrhage, and in glioblastomas to macrophages. Together these data demonstrate that the different primary brain tumors show distinc t regulation of MMP and TIMP genes. The localization of the soluble gelatin ase B indicates an association with neovascularization. whereas membrane-bo und MMPs may account for the invasive potential of the glial tumor cells.