Elsevier

Lung Cancer

Volume 58, Issue 3, December 2007, Pages 384-391
Lung Cancer

Overexpression of matrix metalloproteinase-7 (MMP-7) correlates with tumor proliferation, and a poor prognosis in non-small cell lung cancer

https://doi.org/10.1016/j.lungcan.2007.07.005Get rights and content

Summary

Background

Matrix metalloporteinase-7 (MMP-7) is a member of the MMP family, and it has been reported to play an important role in tumorigenesis, invasion and metastasis. We performed a retrospective study on the MMP-7 expression in non-small cell lung cancer (NSCLC) according to the clinical characteristics, biological markers and the Wnt1 expression.

Patients and methods

One hundred forty-seven postsurgical NSCLC patients were investigated. Immunohistochemistry was performed to evaluate the MMP-7 expression, the Ki-67 proliferation index, tumor angiogenesis and the Wnt1 expression. The TUNEL method was performed to investigate tumor apoptosis.

Results

Seventy-six carcinomas (51.7%) were MMP-7-positive. The MMP-7 expression was significantly higher in squamous cell carcinomas than in adenocarcinomas (P < 0.0001). The Ki-67 proliferation index was significantly higher in MMP-7-positvie tumors than in MMP-7-negative tumors (P = 0.0003). However, there was no difference in the MMP-7 expression in relation to apoptosis or angiogenesis. Regarding its regulation, the MMP-7 expression significantly correlated with the Wnt1 expression (r = 0.426, P < 0.0001). The overall survival was significantly lower in patients with MMP-7-positive NSCLCs than in those with MMP-7-negative NSCLCs (P = 0.0018). A Cox regression analyses also demonstrated MMP-7 status to be a significant prognostic factor (hazard ratio, 2.187; P = 0.0023).

Conclusions

The overexpression of MMP-7 was associated with tumor proliferation, and a poor prognosis in NSCLCs. In addition, Wnt1 may play a critical role in regulating the intratumoral MMP-7 expression.

Introduction

Non-small cell lung cancer (NSCLC) is one of the most common human cancers with a poor prognosis. A surgical resection plays a major role in managing patients with stage I and II NSCLCs, and they are also sometime used for patients with stage III NSCLCs [1]. Various concomitant treatments with chemotherapy and radiotherapy have been assessed to improve the outcome of patients with NSCLCs [2], [3]. However, the 3-year survival rate is 35–50% in patients with stage II NSCLCs and 28% in patients with stage III NSCLCs [4]. Therefore, it is important to clarify the mechanism of tumor biology and find new therapeutic strategies for improving the outcome of NSCLC patients.

Matrix metalloproteinases (MMPs) are a family of highly conserved enzymes that are capable of degrading the extracellular matrix (ECM). Over 25 well-characterized members of this proteinase family have been identified. They play a key role not only in the normal processes of ECM degradation, but also in pathological processes, including tissue remodeling of inflammatory disease, cancer invasion, and metastasis [5], [6]. Substantial evidence has shown an overexpression of MMPs to correlate with a more aggressive phenotype of tumor cells and a poor prognosis in cancer patients. Recently, therapeutic strategies that inhibit the activities of MMPs have been developed [7].

Among these, matrix metalloproteinase-7 (MMP-7) (matrilysin) is the smallest (28 kDa) member of the MMP family. It has broad substrate specificity against ECM components, including elastin, type IV collagen, fibronectin, vitronectin, aggrecan, and proteoglycans [8], [9], [10]. In addition, recent studies have also shown that MMP-7 is also involved in the regulation of several bioactive substances other than ECM. MMP-7 plays an important role in ectodomain shedding of cell-surface molecules, such as epidermal growth factor receptor (EGFR) [11], heparin binding epidermal growth factor (HB-EGF) [12], Fas ligand [13], [14] and E-cadherin [15], [16]. These studies demonstrated MMP-7 to have multiple biological functions, such as tumor invasion and metastasis. Previous clinical studies have shown an overexpression of MMP-7 to correlate with an aggressive phenotype in many malignant tumors, including colorectal cancers [17], [18], gastric cancers [19], [20], esophageal cancers [21], [22] and pancreatic cancers [23], [24]. Furthermore, unlike the other members of the MMP family, MMP-7 is expressed by tumor cells themselves but not by the stromal cells [10], indicating that MMP-7 could be useful as a tumor-associated biological marker and a target of therapeutic intervention.

Despite recent progress in this area, there have so far been few studies on MMP-7 in NSCLCs [25], [26], [27]. A comprehensive analysis of MMP-7 expression in NSCLCs will be necessary to fully understand the biological properties of NSCLCs and to promote the development of new therapeutic strategies. To clarify the role of the MMP-7 in NSCLCs, we performed a retrospective clinical study on MMP-7 expression in relation to the clinical characteristics, biological markers, such as the Ki-67 proliferation index, tumor angiogenesis, and the apoptotic index. Furthermore, MMP-7 is one of targets of the canonical Wnt/β-catenin signaling pathway [28], [29]. An additional evaluation of the Wnt1 expression was performed in relation to the MMP-7 expression in NSCLCs.

Section snippets

Patients

From January 1993 to March 1997, NSCLC patients who underwent surgery at the Second Department of Surgery, Faculty of Medicine, Kagawa University were studied. Tumor-node-metastasis (TNM) staging designations were made according to the international postsurgical pathological staging system [30]. In total, 147 patients with lung cancer up to stage IIIB, which included 86 patients with adenocarcinomas, 51 patients with squamous cell carcinomas, and 10 patients with large cell carcinomas, were

MMP-7 expression in NSCLCs

MMP-7 staining appeared in tumor cells in the form of a heterogeneous cytoplasmic staining pattern (Fig. 1). Regarding the intratumoral MMP-7 expression, the percentage of MMP-7-positive tumor cells varied greatly among the 147 NSCLCs (mean, 43.4 ± 30.0%). Among the 147 carcinomas studied, 76 carcinomas (51.7%) were MMP-7-positive, and 71 carcinomas (48.3%) were MMP-7-negative (Table 1). Regarding tumor histology, the intratumoral MMP-7 expression was 57.8 ± 28.6% in squamous cell carcinomas and

Discussion

MMP-7 has been detected in several normal tissues, such as the endometrium, bronchial mucosa, monocytes, and mesangial cells [8], [10]. It was also identified in a variety of tumors including colorectal cancers [17], [18], gastric cancers [19], [20], esophageal cancers [21], [22], pancreatic cancers [23], [24] and lung cancers [25], [26], [27]. In comparison with other MMPs, MMP-7 is distinguished by its low molecular mass (28 kDa) and its lack of a C-terminal domain [8], [10]. Regarding the

Conflict of interest

All authors affirm that we have no actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within 3 years of beginning the work submitted.

Acknowledgements

This work was supported by Grants-in-Aid for Scientific Research from Japanese Society for the Promotion of Science to C.H. (18390379).

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