Original contributionMembrane-type-1 matrix metalloproteinase, matrix metalloproteinase 2, and tissue inhibitor of matrix proteinase 2 in prostate cancer: identification of patients with poor prognosis by immunohistochemistry
Introduction
With 300 000 new cases every year, prostate cancer (Pca) is the most common cancer in North American men [1]. However, only 2.9% die of their disease [1]. Therefore, more conservative therapies instead of standard radical treatments, such as radical radiotherapy and prostatectomy, may represent an alternative for elderly patients with high-risk surgical conditions. Tumor behavior cannot be accurately and reliably predicted by our current prognostic factors. The identification of new prognostic factors may allow the development of new treatment strategies with less morbidity.
Matrix metalloproteinase (MMP) 2 is part of the MMP family, which includes more than 20 zinc-dependant endopeptidases that degrade various components of the extracellular matrix [2]. MMPs have also been shown to be involved in the release of growth factors that enhance tumor growth and aggressiveness [3]. Because of their proteolytic and growth-factor–releasing activities, MMPs are thought to be involved in cancer progression.
Pro-MMP2 is a 72-kd protein [2] that is cleaved into an active form of 62 kd. Active MMP2 is mostly involved in type IV collagen and gelatin proteolysis [2]. MMP2 has been demonstrated to be up-regulated in many tumor types and is associated with prognosis in most of them [4]. Whereas most MMPs are transcriptionally regulated, MMP2 is constitutively expressed by stromal cells [2]. MMP2 is mainly regulated by its zymogen inhibitor, tissue inhibitor of matrix proteinase 2 (TIMP2), and by its major activator, membrane-type-1 MMP (MMP14) [2]. MMP14 is a membrane-type nonsoluble MMP. According to Strongin et al [5], who showed in 1995 that MMP2 was activated by MMP14, TIMP2 inhibits successively MMP14 and pro-MMP2 molecules, TIMP2 being the link between MMP14 and MMP2. A free adjacent MMP14 then cleaves pro-MMP2 (Asn37-Leu38), leading to an intermediate molecule. A nearby active MMP2 can finally cleave the intermediate form of MMP2 (Asn80-Tyr81), leading to another active MMP. Because of the unique MMP2 activation mode, TIMP2 is involved in MMP14 inhibition when expressed at high levels and in MMP2 activation when expressed at lower levels [5].
We have previously shown that MMP2 overexpression by cancer cells was associated with a poor prognosis in T3N0-2M0 Pca [6]. Our current project was aimed at testing the hypothesis that the balance between MMP2 and the main molecules involved in its activation and/or in its inhibition—MMP14 and TIMP2—are related to Pca disease-free survival (DFS). We hoped that this study might help to identify new potential targets to treat a subset of patients, such as those with a high surgical risk, with a more conservative approach.
Section snippets
Population
The patients included in this retrospective study underwent a radical prostatectomy at l'Hôtel-Dieu de Québec hospital (Quebec City, Canada) between 1991 and 1997 for a pT3N0-2M0 disease, followed by prostate-specific antigen (PSA) serum measurements. Patients were excluded from the study if they had received neoadjuvant hormonal therapy. Patients' charts were reviewed by experienced research nurses to retrieve clinical information (age, tumor stage, initial and follow-up serum PSA level,
Population and tumor characteristics
The initial study population consisted of 207 cases of stage pT3N0-2M0 Pca. Of these, 18 cases were excluded because adequate follow-up was lacking or because the paraffin-embedded specimen was inadequate for analyses, leaving 189 patients for MMP14 analyses, 188 for TIMP2 analyses, and 187 for MMP2. Characteristics of the patient population are shown in Table 1. Median patient age was 64 years (range, 44-74 years), and the mean serum PSA level was 14.5 ng/mL (range, 1.7-126 ng/mL). Thirty-four
Discussion
There is a need to identify new prognostic factors in Pca. However, the influence of MMP expression on Pca survival has rarely been investigated despite growing evidence linking MMP overexpression and poor survival of many tumor types [11], [12], [13], [14], [15], [16], [17], [18], [19]. Wood et al [15] and Ross et al [16] both reported the association between MMP2 and TIMP2 expression and Pca prognosis, but these studies were carried out on small populations with limited follow-up. Boag and
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