Quantitative immunohistochemical and in situ hybridization analysis of metalloproteinases in prostate cancer

Abstract The role of matrix metalloproteinases (MMPs) as markers of tumor progression in prostate cancer (CaP) is complex and poorly understood. Using computerized image analysis, the differential expression of interstitial collagenase (MMP-1), gelatinase B (MMP-9), matrilysin-1 (MMP-7) and the membrane-type 1-MMP (MT1-MMP) in the epithelium and stroma of human prostate neoplastic tissues were investigated. Using immunohistochemistry and in situ hybridization techniques, 38 paraffin-embedded prostatic samples were analyzed and CaP was compared with prostate intraepithelial neoplasia (PIN) and its normal adjacent prostate (NAP) counterpart. The association of MMP protein and mRNA expression with Gleason histological tumor grade and TNM clinical stage was also determined. In most prostatectomy specimens examined, detectable amounts of MMP-1, MT1-MMP, MMP-7 and MMP-9 proteins and MT1-MMP and MMP-9 mRNA were found in the epithelial and stromal components of CaP, PIN and NAP. MMP expression was significantly stronger in the epithelium than in the stroma (p < 0.01). In the epithelium of normal and preneoplastic prostate tissue, MMP-1, MMP-9 and MT1-MMP were preferentially expressed in secretory luminal cells; conversely, MMP-7 was concentrated in basal cells. Epithelial and stromal expressions of MMPs differed in normal, preneoplastic and CaP tissues. Whereas MMP-1 was overexpressed in NAP epithelial glands and progressively decreased from PIN to CaP, MMP-7, MMP-9 and MT1-MMP were more strongly expressed in CaP than in PIN and NAP tissue. The MMPs investigated reached their highest levels in prostate tumors with high Gleason scores. The differential MMP expression in epithelial and stromal prostate tissue supports the previous hypothesis that MMPs may be autocrine and paracrine mediators of the stroma-epithelial interaction, an event that plays a critical role in regulating normal and abnormal prostate growth. MMP gene regulation changes during the early stage of prostate cancer. Differential expression of MMP components in CaP may reflect the malignant phenotype and more aggressive tumor behavior.