CLINICAL VALUE OF STUDY OF MATRIX METALLOPROTEINASES AND THEIR INHIBITORS IN PATIENTS WITH OVARIAN CANCER

Objective: by using quantitative enzyme immunoassays, to comparatively estimate the content of matrix metalloproteinases (MMP)-2, -7, and -9 and their type 1 and 2 tissue inhibitors (TIMP) in the tumors and sera of patients with cancer, benign, or borderline neoplasms of the ovary and to analyze the relationship between these indicators and the major clinical and morphological features of ovarian cancer. Subjects and methods. Eighty-four patients with primary ovarian tumors (49, 11, and 24 patients with malignant, borderline, and benign tumors, respectively) were examined. A control group included 30 apparently healthy women. Out of the 49 patients with malignant ovarian tumors, 43 were found to have serous ovarian carcinoma; 3, mucinous carcinoma; and 3, endometrioid carcinoma. Serous tumors were identified in 19 cases of the 24 benign ovarian neoplasms. The levels of the study proteins were determined in the sera and tumor lysates [12], by applying the standard enzyme immunoassay kits, Human/ Mouse/Rat MMP-2 (total), Human MMP-7 (total), Human MMP-9 (total), Human TIMP-1, and Human TIMP-2 (Quantikine®, R&D Systems, USA). The concentration of the study indicators was expressed as nanograms per ml (ng/ml) for serum and as nanograms per ml total protein (ng/mg protein) for tissues. The data were processed using the software Statistica 7.0. Nonparametric methods, such as Mann-Whitney U test, Kruskal—Wallis H test, and Spearman’s rank order correlation coefficient (R), were used to compare values and to analyze their relationships. The differences and correlations were considered significant at p<0.05. Results. Analysis of the serum content of MMP and TIMP indicated that the most promising marker for the differential diagnosis of borderline, benign, and malignant ovarian neoplasms was MMP-7. The level of this MMP was above the control one only in the patients with ovarian cancer. The level exceeding the upper limit of the reference range (95% of the control values — less than 4.67 ng/ml) was noted in 38 of the 49 primary patients with cancer, i.e. its sensitivity relative to the controls at 95% specificity was 78%. The sensitivity of this test was 37.5 and 64% for benign and borderline neoplasms, respectively. MMP-7 proved to be the most important marker in analyzing the relationship between the serum values and the clinical and morphological features of ovarian cancer. Its level was significantly positively correlated with the key indicators of the extent of ovarian cancer: the stage of the disease as a whole, the size of a primary tumor, as evidenced by ultrasound study, the presence and pattern of peritoneal dissemination and metastases in the greater omentum, and the presence and amount of ascites. The concentration of MMP-7 in the serum was also correlated with that in the ascitic fluid (R=0.53; p=0.008). Furthermore, only the level of MMP-7 was positively associated with that of the classical serum ovarian cancer marker CA-125 (R=0.32; p=0.003). Conclusion. Enzyme immunoassay of MMP-2, MMP-7, and MMP-9 and TIMP-1 and TIMP-2 levels in the tumor tissue and serum of patients with cancer, borderline, or benign neoplasms of the ovary showed a coordinated increase in the tissue expression and serum concentration of MMP-7 in ovarian cancer. The changes opposite in opposite magnitude were found for MMP-2. Those in the levels of MMP-9, TIMP-1, and TIMP-2 were less marked. MMP-7 should be regarded as the most important serological marker for ovarian cancer.

matrix metalloproteinase-2, matrix metalloproteinase-7, matrix metalloproteinase-9, tissue inhibitor of matrix metalloproteinase-1, tissue inhibitor of matrix metalloproteinase-2, ovarian cancer, diagnosis, prognosis