Membrane type 1-matrix metalloproteinase (MT1-MMP) and MMP-2 immunolocalization in human prostate: Change in cellular localization associated with high-grade prostatic intraepithelial neoplasia

Membrane type 1-matrix metalloproteinase (MT1-MMP) is a known activator of latent MMP-2 (pro-MMP-2), and increased MMP-2 expression has been associate d with tumor aggressiveness in prostate cancer. However, expression of MT1- MMP in human prostate tissue has not been described. We investigated the ex pression and immunolocalization of MT1-MMP and MMP-2 in the epithelial comp onents of benign prostate epithelium, high-grade prostatic intraepithelial neoplasia (HGPIN), and prostate cancer. Tissue sections from the peripheral zone of 50 prostates (radical prostatectomy specimens) were chosen based o n their containing benign glands, HGPIN, and prostate cancer glands. All 50 sections were immuuostained for MT1-MMP and MMP-2 and were evaluated for s taining pattern, uniformity, and intensity. Western blotting and gelatin zy mography were done to confirm expression of MT1-MMP and activity of MMP-2, respectively, Comparisons were made between benign epithelium, HGPIN, and c ancer. In benign glands, basal cells (BCs) uniformly stained intensely for MT1-MMP, whereas secretory cells (SCs) were rarely positive (P < 0.0001). C onversely in HGPIN, SCs showed consistent cytoplasmic staining (P < 0.0001) . In cancer cells, staining was heterogeneous and varied from no staining t b very intense staining in select glands. MMP-2 in normal tissue stained bo th BCs and the apical region of SCs, whereas in HGPIN, staining was observe d in the SC in a predominantly cytoplasmic pattern. Similar to MTI-MMP, sta ining in cancer tissue for MnlIP-2 was heterogeneous; however, there was a significant association between the pattern of MMP-2 and MT1-MMP staining w ithin the epithelial components of the cancer glands in individual specimen s (P < 0.001). Finally, MMP-2 and MT1-MMP were confirmed to be expressed in the prostate tissues by gelatin zymography and Western blotting. In conclu sion, we found that consistent changes in localization and intracellular di stribution of MMP-2 and MT1-MMP were associated with the transition from be nign prostate epithelium to HGPIN, suggesting that regulation of these enzy mes is altered during the earliest stages of prostate cancer.