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 matrix and basement membrane degradation, mediated by various classes of proteolytic enzymes. Matrix metalloproteinases (MMP) appear to have a key role in the sequence of events that lead to local invasion and metastasis. The present study evaluated the role of matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinases-2 (TIMP-2), and membrane-type metalloproteinase (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 situ hybridization. MMP-2 protein expression was evaluated using immunohistochemistry. Results were analyzed for possible correlation with disease outcome.


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 exclusively in tumor cells and was uniformly absent from CIN lesions and control cervices. Conversely, intense signals for TIMP-2 and MT1-MMP were detected in both stromal and tumor cells of invasive carcinomas, more often for the former. As with MMP-2, they were absent from CIN lesions. MMP-2 protein expression was enhanced in tumor cells compared to CIN cases and controls, significantly 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 for 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 analysis, MMP-2 presence retained its association with survival (P = 0.004), in addition 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 associated with poor survival.
Davidson
B
B
Affiliated with Sackler School of Medicine, Sheba Medical Center, Tel Hashomer, Israel. bend@ulrik.uio.no
Goldberg
I
I
Kopolovic
J
J
Lerner-Geva
L
L
Gotlieb
W H
WH
Ben-Baruch
G
G
Reich
R
R
D000328:Adult; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000235:genetics*; D005260:Female; D018093:Gelatinases / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020778:Matrix Metalloproteinase 2; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000737:chemistry / Q000235:genetics*; D002578:Uterine Cervical Dysplasia / Q000737:chemistry / Q000235:genetics*
D012333:RNA, Messenger; D019716:Tissue Inhibitor of Metalloproteinase-2; D018093:Gelatinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2