Expression of matrix metalloproteinase-9 in squamous cell carcinoma of theuterine cervix - Clinicopathologic study using immunohistochemistry and mRNA in situ hybridization

Objective. Invasion of the extracellular matrix and blood vessels by malign ant neoplasms, with subsequent distant dissemination, is a key event in tum or progression. This process appears to be mediated largely through the act ion of matrix metalloproteinases (MMPs), a family of proteolytic enzymes pr oduced by both stromal and tumor cells. The role of gelatinases (MMP-2 and MMP-9) in basement membrane and matrix degradation was described in various tumors. We studied MMP-9 protein expression in cervical intraepithelial ne oplasia (CIN) and squamous cell carcinoma using immunohistochemistry and de tected MMP-9 mRNA using in situ hybridization. Methods. Fifty squamous cell carcinomas, 10 cases of CIN II-III, and 10 nor mal cervices were stained for MMP-9, using a monoclonal antibody. The prese nce of MMP-9 mRNA was studied using in situ hybridization. Results were cor related with patient survival during a follow-up period of up to 167 months (average, 41 months). Results. Immunohistochemical staining of tumor cells for MMP-9 was noted in 36/50 (72%) carcinomas and 5/10 (50%) CIN lesions, but was uniformly absen t from the nonneoplastic epithelium adjacent to tumors and from control cer vices. Peritumoral staining of stromal cells was observed in 27/50 (54%) ca rcinomas, but only in 3/10 (30%) CIN lesions and 1/10 (10%) control cervice s. The presence of MMP-9 mRNA was detected in tumor cells in 39 (78%) carci nomas and 8 (80%) CIN lesions, but only in 4 (40%) control cervices. An int ense signal for MMP-9 mRNA was observed most frequently in carcinomas. MMP- 9 mRNA was detected in stromal cells in the majority of cases. However, an intense signal was observed only in stromal cells around invasive tumors. I n survival analysis, age (P = 0.016), grade (P = 0.016), and stage (P = 0.0 01) showed independent correlation with poor survival. Neither MMP-9 protei n expression nor an intense signal for MMP-9 mRNA was associated with poor survival, although the latter was observed more frequently in neoplastic ce lls of lethal tumors (8/14 tumors vs 11/36 nonlethal tumors). Conclusions. MMP-9 mRNA and protein expression are elevated in tumor and st romal cells of both high-grade CIN and invasive squamous cell carcinoma of the uterine cervix. Thus, MMP-9 is possibly an early marker of tumor progre ssion in squamous lesions of the cervix. An intense stromal signal for MMP- 9 mRNA characterizes some invasive carcinomas. Expression of MMP-9 in cervi cal carcinoma cells is present in both lethal and nonlethal tumors, consist ent with the key role of this proteolytic enzyme in invasion, and does not appear to predict disease outcome. (C) 1999 Academic Press.