Japanese Journal of Clinical Oncology Advance Access originally published online on May 30, 2006
Japanese Journal of Clinical Oncology 2006 36(5):263-268; doi:10.1093/jjco/hyl024
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© 2006 Foundation for Promotion of Cancer Research
Association between Cyclooxygenase-2 and Matrix Metalloproteinase-2 Expression in Non-Small Cell Lung Cancer
Departments of Internal Medicine and 1 Clinical Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea
For reprints and all correspondence: Myung Ah Lee, Division of Oncology, Department of Internal Medicine, College of Medicine, Catholic University, Kangnam St Mary's Hospital #505 Banpo-dong, Seocho-gu, Seoul 137–040, South Korea. E-mail: angelamd{at}catholic.ac.kr
Received October 12, 2005; accepted February 8, 2006
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Abstract |
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Background: Cyclooxygenase-2 (COX-2) contributes to invasiveness of cancer through activation of several matrix metalloproteinases (MMPs). Matrix metalloproteinase-2 (MMP-2) is a proteolytic enzyme that degrades the extracellular matrix, and has been linked to invasion and metastasis. This study aims to assess the correlation of the COX-2 expression and the MMP-2 expression in patients with non-small cell lung cancer (NSCLC).
Methods: We analyzed the protein expressions of COX-2 and MMP-2 by immunohistochemical staining on the tissue array specimens from 204 patients with completely resected NSCLC. A <10% immunostaining of the cancer cells was considered negative, while >10% was considered positive.
Results: The COX-2 expression was positive in 68.1% and that of the MMP-2 was positive in 45.6%. The positive expression rate of MMP-2 (52.5%) in the positive COX-2 group was higher than that in the negative COX-2 group (30.8%, P = 0.004). Furthermore, the MMP-2 expression was associated with lymph node involvement, the tumor stage and the histological type. The patients with a positive MMP-2 expression showed a reduced survival (P = 0.048).
Conclusions: The COX-2 expression is associated with the MMP-2 expression in NSCLC patients: the latter may also be associated with tumor progression and reduced survival in NSCLC patients.
Key Words: cyclooxygenase-2 • matrix metalloproteinase-2 • non-small cell lung cancer
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INTRODUCTION |
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Cyclooxygenase (COX) is the key enzyme that converts arachidonic acid into prostaglandins (PGs) and other bioactive lipids, and these PGs are involved in the regulation of normal growth responses and aberrant cellular growth. The COX molecules exist in two isoforms: COX-1 and COX-2, which are derived from distinct genes. COX-1 is the constitutive isoform and it is present in most tissues. COX-1 has been postulated to function as a ‘house-keeping gene’ that is responsible for several physiological functions. Conversely, COX-2 is dramatically up-regulated by a diverse variety of stimuli such as interleukin-1, tumor necrosis factor-
, platelet-derived growth factor, epidermal growth factor, lipopolysaccharide and tumor promoters. The expression of COX-2 has been detected in many different malignancies (1–5), and this has been reported to be associated with tumor growth, resistance to apoptosis, angiogenesis and tumor invasiveness (6–11). In lung cancer, COX-2 expression is found in most stages of tumor progression, and some researchers have found that tumors with the highest COX-2 protein or messenger RNA expression have a worse prognosis (12–14). The matrix metalloproteinases (MMPs) are involved in the degradation of the extracellular membrane, including the basement membrane. Basement membrane is a specialized matrix which is composed of type IV collagen, laminin, entactin, proteoglycans and glycosaminoglycans (15). MMPs belong to a class of transmembrane or secreted endopeptidases, and degradation of the extracellular membrane is thought to be a prerequisite for tumor invasion and metastasis (16,17). Several recent reports have confirmed the involvement of MMPs in non-small cell lung cancer (NSCLC) (18–20). One of the MMPs is matrix metalloproteinase-2 (MMP-2), also known as gelatinase A. MMP-2 has been implicated in the lymphatic and vascular invasion of NSCLC (18), overexpression of which can also predict an unfavorable outcome of patients with early-stage NSCLC (21).
Metastasis is characterized by a number of steps, many of which are dependent upon proteolysis of the basement membrane and other extracellular barriers. Therefore, expression of MMPs in tumor cells is thought to be mandatory for their metastasis. PGs are catalytic products of COX-2 which play important roles not only for regulating MMPs during the normal physiological processes, but also for the regulation of the metastatic potential of cancer cells by regulating the expression of MMPs. In particular, prostaglandin E2 has been reported to regulate the metastatic potential of cells through regulation of MMP-2 (22). Thus, it is possible that COX-2 expression is associated with MMP-2 expression. Indeed, there may exist a direct link between COX-2 and MMP-2 as transfection of COX-2 increases the amount of activated MMP-2 in breast and colon cancer cells (23).
In this study we tried to evaluate the association of the COX-2 expression and the MMP-2 expression by performing immunochemistry on a tissue array of 204 NSCLC specimens.
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METHODS |
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Patients and Tissue Samples
The subjects of this study were a total of 204 patients with NSCLC who underwent surgical resection (lobectomy or pneumonectomy) from 1995 to 2003 at St Mary's Hospital, The Catholic University of Korea. All the specimens examined were obtained from these subjects. We collected the patients' clinicopathological data, including age, gender, the performance status (using the Eastern Cooperative Oncology group scale), and the date of initial diagnosis, histopathological diagnosis, the pathological tumor stage and the date of death from NSCLC or the date of the last follow-up. Histological classification was performed according to the WHO criteria (24), and the post-operative pathological staging was performed according to the International Staging System for lung cancer. The follow-up data were obtained from the medical records.
IMMUNOHISTOCHEMISTRY
The 4 µm thick formalin-fixed and paraffin-embedded tissue sample sections were deparaffinized in xylene, and then treated with 0.3% hydrogen peroxide in methanol for 20 min to block the endogenous peroxidase activity. The sections were next microwaved in citrated-phosphate buffer (pH 6.0) for antigen retrieval and then incubated with 10% normal goat serum for 30 min to block any non-specific binding. Mouse monoclonal antibodies specific for COX-2 (Cayman, Ann Arbor, MI, USA) and MMP-2 (Cayman, Ann Arbor, MI, USA) were then applied as the primary antibodies at a dilution of 1:100 at 4°C overnight, and this was followed by a standard staining procedure using the Vectastain ABC kit (Vector Laboratories, Burlingame, CA). Non-immunized rabbit serum was used for the negative control.
EVALUATION OF THE COX-2 AND MMP-2 EXPRESSIONS
The immunostaining was semi-quantitatively analyzed by verifying the distribution of stained cancer cells in the center of the tumors. The results were independently evaluated by three researchers (KY Lee, AW Lee and GS Park) with the aid of a multiheaded microscope; these researchers were kept unaware of the clinical data. In case of an occasional discrepancy in the interpretation, a consensus was achieved after discussing the findings. The reactions in the smooth muscles and the vascular endothelial cells, which were present in all specimens, were used as internal built-in controls. The distribution of the stained cells in the tumors was divided into four groups: negative when the staining was <10% of the cells, weakly positive when the staining was noted in 10–25% of the cells, intermediate positive when the staining was noted in 26–50% of the cells and strongly positive when the staining was noted in >50% of the cells.
STATISTICAL ANALYSIS
All statistical analyses were carried out with using SPSS (version 11.0) after all the immunohistological evaluations were completed. The 
2 test was used to examine the association between the increased COX-2 and MMP-2 expressions and the various clinicopathological characteristics. The Kaplan–Meier method was used to estimate survival as a function of time, and the survival differences were analyzed with using the log-rank test. All of the statistical tests were two-sided and P values of 0.05 or less were considered to be statistically significant.
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RESULTS |
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PATIENT POPULATION
We examined the tumors from the study subjects (163 men and 41 women, age range: 19–86 years, median age: 64 years). Among the 204 tumors that we examined, 104 (51.0%) were adenocarcinoma, 93 (45.6%) were squamous cell carcinoma and 7 (3.4%) were other types of miscellaneous tumors. With regard to treatment, most of the patients underwent lobectomy. The median follow-up duration was 36 months (range: 1–125 months). Within the observation period, a total of 86 patients died: 82 patients died of cancer-related causes, 1 patient died as a result of complications of surgery, 1 patient died of radiation complications and 4 patients died of no definitive cause without disease relapse.
EVALUATION OF THE COX-2 AND MMP-2 IMMUNOHISTOCHEMICAL STAINING
The tumor specimens of the 204 cases were assayed for COX-2 and MMP-2 expressions by performing immunohistochemical staining. For COX-2 expression, 43 (21.1%) cases had a strong expression, 32 (15.7%) cases had an intermediate expression, 64 (31.4%) cases had a weak expression and 65 (31.9%) cases had a negative expression. For MMP-2 expression, 46 (22.5%) cases had a strong expression, 30 (14.7%) cases had an intermediate expression, 10 (4.9%) cases had a weak expression and 118 (57.8%) cases had a negative expression (Fig. 1).
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ASSOCIATION WITH THE CLINICOPATHOLOGICAL PARAMETERS
We tested for the correlation between the COX-2 and MMP-2 expressions and such clinical and pathological parameters as tumor extension, lymph node involvement, staging, tumor histology, age and gender. There was no significant correlation for the COX-2 expression with the clinicopathological parameters, but the MMP-2 expression was associated with the lymph node involvement (N0 versus N1–2: 39.5 versus 56%, P = 0.023), the disease stage (stage I versus stage II–III: 37.6 versus 56.3%, P = 0.008) and tumor histology (adenocarcinoma versus non-adenocarcinoma: 57.7 versus 33.3%, P = 0.002) (Tables 1 and 2). Although there was no statistically significant difference for survival according to the COX-2 expression (P = 0.92), the MMP-2 expression was associated with a worse survival (P = 0.048) (Fig. 2). The multivariate regression analysis demonstrated that age and the disease stage were the significant (P < 0.05) independent prognostic predictors for survival. On the multivariate analysis, the COX-2 and MMP-2 expressions were not found to be statistically significant independent prognostic factors, but the MMP-2 expression showed a tendency towards being a prognostic factor (P = 0.056).
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ASSOCIATION OF THE COX-2 EXPRESSION AND THE MMP-2 EXPRESSION
On further analysis for testing the relationships between the COX-2 and MMP-2 expressions and the clinicopathological features, we simply divided the cases into two groups: the negative expression group versus the positive expression group. For the COX-2 and MMP-2 expressions, <10% immunostaining of the cancer cells for either COX-2 or MMP-2 was considered negative and >10% immunostaining of the cancer cells for either COX-1 or MMP-2 was considered positive. A statistically significant association was found between these two factors (Table 3, P = 0.004).
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DISCUSSION |
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After neoplastic transformation, the tumor–host interactions promote a series of coordinated molecular and cellular processes that underlie a continuum of steps that define the metastatic spread of disease. These interrelated steps that are required for metastasis are similar for all types of tumor, and they include tumor cell attachment, neovascularization for further tumor growth, disruption of the basement membrane with subsequent invasion of malignant cells into the host stroma, intravasation into the blood or lymphatic circulation, survival and transport within the circulation, extravasation at distant sites and then growth within the new environment (25).
A direct link between COX-2 and MMP-2 has been shown to exist in several experimental models. Masferrer et al. (7) have reported that COX-2 stimulates endothelial cell migration and vessel tube formation, and these processes are inhibited by non-steroidal anti-inflammatory drugs. They also reported that COX-2 affects the MMP-2 levels and the activated collagenase levels. That study found that the expressions of VEGF and MMP-2 in the COX-2 positive group were significantly higher than that in the COX-2 negative group. Tsujii et al. (23) showed that human colon cancer carcinoma cells that were transfected with a COX-2 expression vector had an increased prostaglandin production and they acquired greater invasiveness as compared with the control cells. Additionally, COX-2 overexpression increased the MMP-2 expression/activation and cellular invasiveness in the colon cancer cells. When these cells were treated with sulindac sulfide, the increased invasiveness was almost completely inhibited in a dose-dependent fashion. In addition, a recent study showed that the COX-2 selective inhibitor rofecoxib can reduce metastasis and decrease the expression of MMP-2 in a mouse model of colorectal cancer (26). Thus, COX-2 derived prostaglandins seem to induce both the MMP-2 expression and its activity. The administration of COX-2 inhibitors has also been shown to suppress the MMP-2 expression and the invasiveness of the cells derived from lung cancer (27).
In this study, we show that expression of COX-2 protein is associated with the expression of MMP-2 protein in NSCLC, and the positive expression rate of MMP-2 (52.5%) in the positive COX-2 group was higher than that in the negative COX-2 group (30.8%, P = 0.004). Furthermore, although the COX-2 expression was not associated with the clinicopathological parameters and patient survival, the MMP-2 expression was associated with the nodal status, disease stage and patient survival. Similarly, Miyata et al. (28) have shown that expression of COX-2 was correlated with the expression of MMP-2 in renal cell carcinoma and that both of these factors were associated with reduced survival. Also, Sivula et al. (29) have shown that the expressions of COX-2 and MMP-2 were associated with reduced survival for human breast cancer and there was a positive association between the expressions of these two factors. This indicates that COX-2 can also lead to alterations in the invasive potential of NSCLC through up-regulating the expression of MMP-2.
In this study, we analyzed the MMP-2 expression in cancer cells. The sites of MMP-2 immunohistochemical staining were the stromal fibroblasts and the tumor cells. Controversy still exists as to which site of MMP-2 expression is associated with tumor invasion and survival for patients with lung cancer. Passlick et al. (21) reported that detection of MMP-2 protein in the malignant cells of NSCLC predicted an unfavorable outcome for early-stage NSCLC. However, Ishikawa et al. (30) have recently reported that detecting MMP-2 in the stromal fibroblasts and not in tumor cells was a significant factor to predict a poor post-operative survival for NSCLC patients. Although it was initially believed that the MMPs derived from the tumor cells played principal roles in tumor progression, recent experimental studies have revealed that stromal cells also express MMPs, especially MMP-2, and that the MMPs derived from the stromal cells play an equal or more important role (31).
Although there was correlation between the COX-2 expression and MMP-2 expression in this study, only the MMP-2 expression was correlated with the prognosis, lymph node metastasis and the histological type. The prognostic role of the COX-2 expression in NSCLC remains controversial. Achiwa et al. (12) have indicated that an increased COX-2 expression may be clinically significant for the prognosis of patients undergoing surgical resection, particularly for patients with stage I adenocarcinoma. However, Marrogi et al. (32) have reported there was no association between the COX-2 expression and the clinical outcome for patients with NSCLC. Our data also indicated that there was no association between the COX-2 expression and the clinical outcome. There are several possible explanations for this result. First, the study population that was analyzed by Achiwa et al. (12) consisted of patients with stage I–IIIa adenocarcinoma, whereas the patients with NSCLC were included in our study, i.e. a correlation between the elevated COX-2 expression and a shortened survival of adenocarcinoma patients was found for stage I disease, but not for advanced stage II/III disease. Second, the proportion of adenocarcinoma cells with a marked COX-2 expression was much greater in lymph node metastases than in the corresponding primary tumors, and this possibly reflected the clinical and molecular pathogenetic complexities of the advanced disease (33).
In conclusion, this study revealed that there was a statistically significant association between the COX-2 expression and the MMP-2 expression in NSCLC patients, and the MMP-2 expression was associated with progression of the tumor stage and the reduced patient survival.
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Acknowledgments |
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This study was supported by a grant from The Catholic University, St's Mary Hospital Clinical Institute Research Fund.
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References |
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