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Matrix metalloproteinase-2 (MMP-2), a collagen-degrading enzyme, is involved in tissue degradation and has been associated with tumourigenesis and metastasis. The functional activity of MMP-2 is inhibited by the tissue inhibitor of metalloproteinase (TIMP) family. In particular, TIMP-2 binds non-covalently to a latent proform of MMP-2 and inhibits its activation. Disruption of the fine balance between MMP-2 and TIMP-2 may be a significant factor in determining the aggressive phenotype of a tumour. The aim of this study was to localise the expression of MMP-2 and TIMP-2 and to compare their levels of expression in benign and malignant prostate tissue. Tissue was obtained from transurethral resection or radical prostatectomy specimens. 47 men were investigated. Tissue from 20 of these was used for localisation of MMP-2 and TIMP-2 mRNA by non-isoptopic in situ hybridisation (ISH); 13 had newly diagnosed and untreated prostate cancer, 7 had benign prostatic hyperplasia (BPH). Tissue from 27 men was used for quantification of mRNA by northern analysis; 21 had cancer and 6 had BPH. MMP-2 and TIMP-2 were expressed by malignant cells in both low and high grade tumours. In low grade tumours, the signal was localised at the luminal edge. TIMP-2 and MMP-2 were also found to be expressed within areas of perineural and extracapsular invasion. Positive signals for both genes were detected in epithelial cells of benign glands and ejaculatory ducts. Benign tissue adjacent to areas of cancer and stromal tissue were negative with all probes. The levels of expression of MMP-2 increased significantly with increasing Gleason score. There was no significant correlation between TIMP-2 and tumour grade. The ratio of MMP-2 to TIMP-2 levels in BPH was 1, and increased from 0.71 in the well-differentiated tumours to 3 in the poorly differentiated tumours. Expression of these genes in areas of perineural and extracapsular invasion suggests that these enzymes may play a significant role in the process of invasion in prostate cancer. The ratio of MMP-2 to TIMP-2 in BPH indicate that there is an established balance of expression in non-malignant prostatic tissue. The changes in MMP-2 to TIMP-2 ratio, in relation to tumour grade suggests an attempt by prostatic tissue to inhibit MMP-2 activity in well differentiated cancers. As tumour de-differentiation occurs it is possible that this inhibitory activity diminishes allowing uncontrolled expression of MMP-2 necessary for tumour invasion.


Journal article


British Journal of Urology

Publication Date