Tissue Inhibitor of Matrix Metalloproteinase-2 in Nasopharyngeal Carcinoma

Amr Ahmed El Badry, MD; Amal Abou El-Fadle, MD; Abdel Latif El-Balshy, MD

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Discussion

ECM turnover is an event that is tightly regulated. Much of the coordinate physiologic or discoordinate pathologic degradation of the ECM is catalyzed by class of proteases known as metalloproteinases. MMPs are a family of multidomain enzymes that are controlled by a class of specific tissue inhibitors of MMPs (TIMPs). TIMP-2 is an endogenous regulator and a potent inhibitor of MMPs.[21]

Recent in vitro studies[22,23,24] have clarified the mechanism of cell-mediated MMP-2 activation in tumor tissue, ie, pro-MMP-2 secreted by fibroblasts binds to TIMP-2 in combination with MT1-MMP on the cell surface, and the pro-MMP-2/TIMP-2/MT1-MMP ternary complex is formed. The pro-MMP-2 in the ternary complex is activated by adjacent MT1-MMP that is free from TIMP-2,[22,23,24] and the activated MMP-2 degrades ECM components. Therefore, on the basis of this theory, the significant association between MMP-2 expression and the expression of either MT1-MMP or TIMP-2 observed here is very reasonable. On the other hand, it is reported that different transcriptional regulation of MMP-2 and MMP-9 genes may be due to the presence of different promoter elements.[25]

In the present study, we attempted to demonstrate a correlation between TIMP-2 protein positivity and the incidence of NPC. We used Western blot analysis to evaluate the expression of TIMP-2 protein in cell lysate from tissue biopsies (from 30 NPC patients and 20 controls). The percent positivity of TIMP-2 protein was statistically highly significant (P < .01) in cancer patients (76.6%) compared with the controls (30%).

This result is consistent with that reported by Katayama and colleagues,[26] who found marked expression of MMP-2 and tissue inhibitor of MMP-2 in early-stage oral SCC. These MMP family members were mainly expressed on the cell surface and in the cytoplasm of tumor cells as well as on some endothelial cells or on the stromal fibroblasts surrounding tumor cells.

In addition, results of TIMP-2 expression in other malignant tumors confirmed the findings of the present study. The expression of TIMP-2 protein was found to be significantly higher in ovarian carcinoma,[27] prostatic adenocarcinoma,[28] thyroid cancer,[29] colorectal cancer,[30] and breast cancer.[31]

In general, TIMP-2 had been believed to suppress tumor invasion and metastasis by inhibiting MMP-2, because TIMP-2 inhibits collagenolysis activity of MMP-2 in vitro.[32] However, according to the model of cell-mediated MMP-2 activation, pro-MMP-2 bound to the TIMP-2/MT1-MMP complex is activated by MT1-MMP that is free from TIMP-2. The activated form of MMP-2 is inactivated by the attachment of TIMP-2.[22,23,24] Recently, high activation of MMP-2 in tongue SCC samples, detected by gelatin zymographic assay, has been reported to be associated with high expression of TIMP-2 in tumor cells.[15] Therefore, the immunoreactivity of TIMP-2 is likely to be useful for monitoring MMP-2 activation.

Moreover, in an attempt to determine the possible role of TIMP-2 protein expression in regional lymph node and/or distant metastasis and in progression of NPC, we tried to find a correlation between percent TIMP-2 protein positivity and either clinical staging or histopathologic typing. Indeed, we found a positive significant correlation with both clinical staging and histopathologic typing: the percentage of protein positivity increased with their gradual increase (P < .01). Our results are in accordance with those reported in recent immunohistologic studies,[14,33,34,35,36] indicating that TIMP-2 plays a positive role in tumor metastasis and that high expression of TIMP-2 correlates with lymphatic invasion and lymph node metastasis. Kallakury and colleagues[37] and Kamayama and colleagues[38] also found a significant correlation between TIMP-2 expression and advanced bladder cancer stage (P < .05).

By contrast, Grignon and colleagues,[39] and Ree and colleagues[40] found that TIMP-2 expression did not correlate with the stage and grade of bladder cancer and breast cancer, respectively, and Oberge and colleagues[41] reported that TIMP-2 protein expression had no significant association with the stage of colorectal cancer and therefore concluded that TIMP-2 protein may be of limited value in colorectal tumor staging.

In summary, the results of our study suggest that TIMP-2 may participate in regional lymph node and/or distant metastasis and may be a useful marker of severity of SCC, but further studies are needed to investigate the role of TIMP-2 in tumor progression and to evaluate its potential value in the follow-up of NPC patients.

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