Expression of matrix metalloproteinase-9 in squamous cell carcinoma of the uterine cervix-clinicopathologic study using immunohistochemistry and mRNA in situ hybridization.
OBJECTIVE
Invasion of the extracellular matrix and blood vessels by malignant neoplasms, with subsequent distant dissemination, is a key event in tumor progression. This process appears to be mediated largely through the action of matrix metalloproteinases (MMPs), a family of proteolytic enzymes produced 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 neoplasia (CIN) and squamous cell carcinoma using immunohistochemistry and detected MMP-9 mRNA using in situ hybridization.


METHODS
Fifty squamous cell carcinomas, 10 cases of CIN II-III, and 10 normal cervices were stained for MMP-9, using a monoclonal antibody. The presence of MMP-9 mRNA was studied using in situ hybridization. Results were correlated 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 absent from the nonneoplastic epithelium adjacent to tumors and from control cervices. Peritumoral staining of stromal cells was observed in 27/50 (54%) carcinomas, but only in 3/10 (30%) CIN lesions and 1/10 (10%) control cervices. The presence of MMP-9 mRNA was detected in tumor cells in 39 (78%) carcinomas and 8 (80%) CIN lesions, but only in 4 (40%) control cervices. An intense 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. In survival analysis, age (P = 0.016), grade (P = 0. 016), and stage (P = 0.001) showed independent correlation with poor survival. Neither MMP-9 protein expression nor an intense signal for MMP-9 mRNA was associated with poor survival, although the latter was observed more frequently in neoplastic cells of lethal tumors (8/14 tumors vs 11/36 nonlethal tumors).


CONCLUSIONS
MMP-9 mRNA and protein expression are elevated in tumor and stromal 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 progression in squamous lesions of the cervix. An intense stromal signal for MMP-9 mRNA characterizes some invasive carcinomas. Expression of MMP-9 in cervical carcinoma cells is present in both lethal and nonlethal tumors, consistent with the key role of this proteolytic enzyme in invasion, and does not appear to predict disease outcome.
Department of Pathology, Sheba Medical Center, Tel Hashomer, Affiliated to Sackler School of Medicine, Tel-Aviv University, Israel.
B
B
Davidson
I
I
Goldberg
J
J
Kopolovic
L
L
Lerner-Geva
W H
WH
Gotlieb
B
B
Weis
G
G
Ben-Baruch
R
R
Reich
D000328:Adult; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D016022:Case-Control Studies; D017364:Collagenases / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020780:Matrix Metalloproteinase 9; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000032:analysis; D016019:Survival Analysis; D002583:Uterine Cervical Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D002578:Uterine Cervical Dysplasia / Q000201:enzymology* / Q000401:mortality / Q000473:pathology
D012333:RNA, Messenger; D017364:Collagenases; D020780:Matrix Metalloproteinase 9