MMP-2 and TIMP-2 expression correlates with poor prognosis in cervical carcinoma - A clinicopathologic study using immunohistochemistry and mRNA in situ hybridization

Objective. The spread of malignant neoplasms is closely associated with mat rix and basement membrane degradation, mediated by various classes of prote olytic enzymes. Matrix metalloproteinases (MMP) appear to have a key role i n the sequence of events that lead to local invasion and metastasis. The pr esent study evaluated the role of matrix metalloproteinase-2 (MMP-2), tissu e inhibitor of metalloproteinases-2 (TIMP-2), and membrane-type metalloprot einase (MT1-MMP) in cervical neoplasia. Methods. We have analyzed 49 uterine cervical squamous cell carcinomas, 10 cases of high-grade cervical intraepithelial neoplasia (CIN II-III), and 10 control cervices for the presence of MMP-2 TIMP-2, and MT1-MMP using in si tu hybridization. MMP-2 protein expression was evaluated using immunohistoc hemistry. Results were analyzed for possible correlation with disease outco me. Results. MMP-2, TIMP-2, and MT1-MMP mRNA were localized to both stromal and tumor cells. However, an intense signal for MMP-2 was detected almost excl usively in tumor cells and was uniformly absent from CIN lesions and contro l cervices. Conversely, intense signals for TIMP-2 and MT1-MMP were detecte d in both stromal and tumor cells of invasive carcinomas, more often for th e former. As with MMP-2, they were absent from CIN lesions. MMP-2 protein e xpression was enhanced in tumor cells compared to CIN cases and controls, s ignificantly compared to the latter (P = 0.01). The presence of both MMP-2 and TIMP-2 mRNA in tumor cells correlated with advanced stage (P = 0.003 fo r MMP-2, P = 0.002 for TIMP-2) and with poor survival (P = 0.003 for MMP-2, P = 0.002 for TIMP-2) in univariate analysis. In addition, their presence in tumor cells intercorrelated (P = 0.002). In multivariate survival analys is, MMP-2 presence retained its association with survival (P = 0.004), in a ddition to patient age (P = 0.027) and advanced stage (P = 0.0002). Conclusions. Both MMP-2 and TIMP-2 have a key role in extracellular matrix invasion in cervical carcinoma, largely through their elaboration by tumor cells. The presence of mRNA for both proteins is interrelated and is associ ated with poor survival. (C) 1999 Academic Press.