Clinical Study
Matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-2: Prognostic biological markers in invasive prolactinomas

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Abstract

In this study, the predictive roles of matrix metalloproteinase (MMP)-9 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 and 2 in invasive and noninvasive prolactinomas were examined. Prognostic biomarkers to distinguish between invasive and noninvasive pituitary adenomas are required for the effective treatment of pituitary adenoma patients. We analyzed 57 prolactinoma patients classified as having invasive and noninvasive adenomas for MMP-9, TIMP-1 and TIMP-2 expression using immunohistochemical methods. Significantly higher MMP-9 expression was detected in invasive prolactinomas (p = 0.004). There was also a significant relationship between TIMP-2 expression and invasive behavior (p = 0.004) and TIMP-2 expression and recurrence (p = 0.005). Because MMP-9 expression is significantly increased in invasive prolactinomas, MMP-9 has potential as a marker for invasion. TIMP-2 may be a marker for both invasion and recurrence. These findings require further examination in large scale prospective studies.

Introduction

Pituitary adenomas are common neoplasms. Although they are generally benign in nature, they may invade adjacent tissues. Recurrence and resistance to treatment are serious problems in invasive pituitary adenoma patients, therefore, when treating pituitary adenomas, biological markers are needed to indicate the invasiveness of the tumor to effectively guide surgical, medical, and radiotherapy treatment modalities and to prevent recurrence. Pituitary adenomas are epithelial tumors that arise from the adenohypophysis. The most frequently detected pituitary adenomas are prolactinomas [1]. Prolactinoma treatment is primarily with dopamine agonist drugs (DA; cabegoline, bromocriptine) [2], [3].

In this study, prolactinomas were investigated with a focus on the roles of matrix metalloproteinase (MMP)-9 and tissue inhibitor of matrix metalloproteinase (TIMP)-2 in pituitary adenoma invasion. Only prolactinomas were investigated in order to concentrate the research on the roles of MMP-9 and TIMP-2 in pituitary adenoma invasion.

The MMP family consists of zinc and calcium-dependent endopeptidases. These enzymes are associated with proteolytic degradation of the extracellular matrix (ECM) [4]. The role of MMP in tumor invasion and metastatic processes has been confirmed. ECM degradation by MMP is a critical process in the progression of malignant tumors, angiogenesis, and tumor invasion and metastasis. Gelatinases (MMP-9 and MMP-2) are thought to be key enzymes in ECM degradation as they degrade some of the main components of the ECM [5], [6]. TIMP are low molecular weight proteins that are secreted and bind to active MMP, inhibiting their enzymatic activity [7].

Moreover, MMP-2 and MMP-9 are unique among the MMP in that the latent forms of these proteinases can form complexes with TIMP-2 and TIMP-1, respectively. In addition to their inhibitory role, TIMP can also take part in the activation of MMP [8]. TIMP-2 is a powerful inhibitor of MMP activity and high levels of TIMP-2 are positively correlated with an unfavorable prognosis in cancer patients [9], [10].

Previous studies have investigated MMP-9, TIMP-1 and TIMP-2 as prognostic biological markers in breast, lung, colon and many other cancer types, and the correlations of these enzymes with invasion and metastasis have been determined [11], [12], [13], [14]. However, MMP-9 studies in pituitary adenomas have yielded conflicting results and TIMP-1 and TIMP-2 have not been studied as potential prognostic biological markers in pituitary adenomas.

In this study, we evaluated the presence of MMP-9, TIMP-1 and TIMP-2 in invasive and noninvasive prolactinomas and investigated their potential as prognostic predictors using immunohistochemical methods.

Section snippets

Methods and materials

In the present study, we retrospectively reviewed the records of patients with prolactinoma who had undergone endoscopic transsphenoidal surgery in the Department of Neurosurgery, Kocaeli University School of Medicine between 1999 and 2011. Fifty-seven patients who were diagnosed with prolactinoma based on clinical, radiological and pathological data were included in this study. The mean ages of the patients in the invasive prolactinoma and noninvasive prolactinoma groups were 43.2 years and 35 

MMP-9 and invasion

MMP-9 expression was detected in all patients (57; 100%). The relationship between MMP-9 expression and invasive behavior was evaluated by the extent of MMP-9 staining measured as the number of adenoma cells showing MMP-9 immunoreactivity. Figure 1 shows MMP-9 staining in one invasive and one noninvasive patient. In invasive prolactinomas, diffuse staining was detected in 85.7% of patients (30/35). A significant relationship was determined between MMP-9 expression and invasive behavior (p = 

Discussion

Pituitary adenomas account for 20% of all intracranial tumors and 40–60% of pituitary adenomas are prolactinomas. Invasion is the most important prognostic factor in pituitary adenoma patients. Approximately 30–35% of functional pituitary adenomas and >50% of nonfunctional pituitary adenomas are associated with dural invasion. Total resection is more difficult for invasive than noninvasive tumors and post-surgery recurrence is common [17], [18]. Surgical complications, the inability to achieve

Conclusion

We conclude that MMP-9 and TIMP-2 can act as prognostic biomarkers of invasive behavior in pituitary adenomas, especially prolactinomas. TIMP-2 can also indicate recurrence risk but this should be confirmed by further large scale studies. MMP-9 expression was shown to be reduced by DA and the correlation between MMP-9 staining intensity and invasion was hampered by DA treatment during the preoperative period. Further research is also needed to determine if MMP-9 expression is reduced by DA.

Conflicts of Interest/Disclosures

The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.

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