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10.1245/s10434-006-9030-z
Annals of Surgical Oncology 13:1517-1523 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Maspin Expression and Its Clinical Significance in Non-Small Cell Lung Cancer

Masatsugu Nakagawa, MD1, Hiromichi Katakura, MD, PhD1, Masashi Adachi, MD1, Kazumasa Takenaka, MD1, Kazuhiro Yanagihara, MD, PhD1,2, Yosuke Otake, MD, PhD3, Hiromi Wada, MD, PhD1 and Fumihiro Tanaka, MD, PhD1

1 Department of Thoracic Surgery, Kyoto University, 54 Shogoin Kawara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
2 Department of Translational Clinical Oncology, Kyoto University, 54 Shogoin Kawara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
3 Department of Thoracic Surgery, Seishin-Iryo Center Hospital, 5-7-1 Kojidai, Nishi-ku, Kobe, Hyogo, 651-2273, Japan

Correspondence: Address correspondence and reprint requests to: Fumihiro Tanaka, MD, PhD; Department of Thoracic Surgery, Hyogo College of Medicine, Mukogawa-cho 1-1, Nishinomiya, 663-8501, Japan; E-mail: ftanaka{at}hyo-med.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Maspin is a member of the serpin (serine protease inhibitor) superfamily, and its exact function in the development and progression of malignant tumors remains controversial, though some experimental studies have revealed potential tumor-suppressor activities. In addition, there have been only a few clinical studies on maspin expression in malignant tumors including non-small cell lung cancer (NSCLC). The purpose of this study was to assess maspin expression and its clinical significance in NSCLC.

Methods: A total of 210 consecutive patients with completely resected pathological (p-) stage I-IIIA NSCLC were retrospectively reviewed. Maspin expression along with intratumoral microvessel density, proliferative activity, and p53 status were evaluated immunohistochemically. The incidence of apoptotic cell death was also evaluated.

Results: The incidence of strong maspin expression was significantly higher in lung squamous cell carcinoma (56/76, 73.7%; P < .001) than in other histological types. The incidence of aberrant expression of p53 was significantly higher in maspin-strong than in maspin-weak tumors (56.2% and 35.8%, respectively; P = .005). There was no difference in prognosis according to maspin status for all patients. However, for squamous cell carcinoma patients, univariate analysis showed that enhanced maspin expression was a significant factor in predicting a favorable prognosis (5-year survival rates, 70.1% for maspin-strong tumors and 41.5% for maspin-weak tumors; P = .014), which was confirmed in a multivariate analysis (hazard ratio = .475, 95% confidence interval .241–.936; P = .032).

Conclusions: Enhanced maspin expression was a significant and independent factor in predicting a favorable prognosis in lung squamous cell carcinoma.

Key Words: Maspin • Tumor suppressor • Non-small cell lung cancer • p53 • Prognostic factor


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Non-small cell lung cancer (NSCLC) accounts for 80–85% of primary lung cancers, which is the leading cause of cancer death in most industrialized countries.1 To improve the poor prognosis of NSCLC patients, clinical markers that can predict prognosis and response toward a specific therapy should be established. Although a variety of biological markers, including p53 abnormality, have been investigated, no biological marker has been established as a clinical marker in the treatment of NSCLC,2 and only mutations of the epidermal growth factor receptor (EGFR) gene may be a promising clinical marker in correlation with the efficacy of EGFR-inhibiting small molecules such as gefitinib.3–5

Protease and protease inhibitors play important roles in the progression of malignant tumors as pro-tease may promote tumor invasion and/or metastasis through degradation of extracellular matrix (ECM) and protease inhibitors antagonize the process. Serine proteases are well-known proteases that participate in tumor progression, and maspin is a unique member of the serpin (serine protease inhibitor) superfamily.6 The maspin gene was originally isolated from normal human mammary epithelial cells by subtractive hybridization, and it has been shown to have tumor-suppressor activity attributable to the inhibition of breast cancer cell motility, invasion, and metastases.7–9 In immunohistochemical studies as well, ma-spin expression was downregulated along with tumor progression of breast cancer.6,10 Thus, in some malignant tumors, such as breast cancer, maspin may act as a tumor suppressor. In contrast, some studies have demonstrated that maspin expression is enhanced along with development of pancreatic cancer,11 and some clinical studies have revealed that enhanced expression of maspin and/or maspin gene is correlated with poor prognosis in breast cancer12,13 and ovarian cancer.14 In addition, a clinical study on breast cancer has shown that enhanced nuclear ma-spin expression is associated with favorable prognostic factors whereas enhanced cytoplasmic maspin expression is associated with poor prognostic factors.15 These conflicting experimental and clinical results indicate that exact roles of maspin in the development and progression of malignant tumors remain controversial.

In primary lung cancer, only a few studies have been reported.16–18 In these studies, some normal epithelial cells in the lung do express maspin, but the clinical significance of maspin expression in the development and progression of lung cancer remains unclear. Thus, in the present study, we evaluated maspin expression immunohistochemically in correlation with clinicopathological features of resected NSCLC patients.


   MATERIAL AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Clinical Characteristics of Patients
A total of 210 patients with pathological (p-) stage I-IIIA NSCLC who underwent complete tumor resection without any preoperative therapy at Kyoto University Hospital between 1985 and 1990 and whose histological specimens are available for immunohistochemical staining (IHS) were retrospectively reviewed (Table 1Go). Pathological stage was reevaluated and determined with the current TNM classification.19 Histological type and the grade of cell differentiation were determined according to the classification of the World Health Organization.20 For all these patients, the inpatient medical records, chest X-ray films, whole-body computed tomographic films, bone and gallium scanning data, and records of surgery were reviewed. Follow-up of postoperative clinical course was conducted by out-patient medical records and by inquiries by telephone or letter.


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  		TABLE 1. Characteristics of patients and maspin expression
 
For histological examination, specimens were fixed in 10% (vol/vol) formalin and then embedded in paraffin. Serial 4-µm sections were prepared from each sample and served for routine hematoxylin and eosin (HE) staining, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) staining, and IHS. This study was reviewed and approved by the Ethics Committee, Graduate School and Faculty of Medicine, Kyoto University.

Evaluation of Maspin Expression
Maspin expression was evaluated with IHS using a streptavidin-biotinylated horseradish peroxidase detection system (LSAB+ kit/HRP; Dako, Kyoto, Japan) following the manufacturer’s protocol. After retrieval of the antigen with heating in a microwave oven for 5 minutes three times each,21 dewaxed sections were incubated overnight at 4° C with an antimaspin polyclonal antibody (C-20, goat immunoglobulin G [IgG] 200 µg/mL; Santa Cruz Bio-technology, San Diego, CA) diluted at 1/400; for negative control slides, the primary antibody was omitted. As a chromogen, diaminobenzidine-tetra-hydrochloride (.03%) containing .1% hydrogen peroxide was used, and sections were counterstained with hematoxylin. Maspin expression in tumor cells was classified based on the staining intensity as follows:–, no staining detected; ±, weak staining; +, moderate staining; ++, high staining. The status of maspin expression in tumor cells was finally classified as weak (– or ±) or strong (+ or ++). Slides were evaluated by two authors independently (M.N. and H.K.) without knowledge of any clinical data.

Detection of Apoptotic Cells
Apoptotic cells were detected with the TUNEL method, as described previously.21 TUNEL staining was performed with the In Situ Death Detection Kit, POD (Boehringer-Mannheim, Mannheim, Germany) following the manufacturer’s protocol. The specificity of TUNEL staining of apoptotic cells was confirmed by making negative and positive control slides at every staining. As negative control slides, sections incubated with the TUNEL reaction mixture without terminal deoxynucleotidyl transferase were used. As positive control slides, sections were treated with DNase I .7mg/mL (Stratagene, La Jolla, CA) for 10 minutes at 25° C before the TUNEL reaction. Evaluation of apoptotic cells was performed as described previously;21 TUNEL positive-staining cells, if they represented the histological features of necrosis in HE-stained sections, were not considered apoptotic. The apoptotic index (AI) was defined as the number of apoptotic cells per 1,000 tumor cells.

Quantification of Angiogenesis and Proliferative Activity
Intratumoral microvessel density (IMVD), a measurement of tumor angiogenesis, was evaluated as described previously;22 IHS for CD34 to highlight endothelial cells (ECs) was performed using a sensitive streptavidin-biotinylated horseradish peroxidase complex system (TSATM-Indirect Kit; NEN Life Science Products, Boston, MA). Briefly, dewaxed sections were incubated with anti-CD34 monoclonal antibody (mAb) QBEnd10 (mouse IgG1{kappa}; Dako) diluted at 1/50. The 10 most vascular areas within a section were selected for evaluation of angiogenesis, and vessels labeled with the anti-CD34 mAb were counted. The average counts were recorded as IMVD for each case.

Proliferative activity of tumor cells was also evaluated immunohistochemically as described previously;21 anti-proliferative cell nuclear antigen (PCNA) mAb PC-10 (mouse IgG2a{kappa}, 400 µg/mL; Dako) diluted at 1/50 were used as primary antibody. The proliferative index (PI) was defined as the percentage of PCNA-positive cells (%).

Evaluation of p53 Status
Status of p53 expression was also evaluated immunohistochemically as described previously.21 An anti-human p53 mAb (clone DO-7, mouse IgG2b{kappa}, 250 µg/mL; Dako) diluted at 1/50 was used as the primary antibody. When the percentage of positive-staining cells exceeded 5%, the slide was judged to exhibit aberrant expression of p53.

Statistical Analysis
Counts were compared by the {chi}2 test. Continuous data were compared using Student’s t-test if the sample distribution was normal or the Mann-Whitney U-test if the sample distribution was asymmetrical. The postoperative survival rate was analyzed by the Kaplan-Meier method, and differences in survival rates were assessed by the log-rank test. Multivariate analysis of prognostic factors was performed using Cox’s regression model. Differences were considered significant at P < .05. All statistical manipulations were performed using the SPSS for Windows software system (SPSS Inc., Chicago, IL).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Expression of Maspin in NSCLC
Maspin expression was detected in the cytoplasm of tumor cells (Fig. 1Go). Maspin expression was strong in 73 patients (34.8%). The incidence of strong ma-spin expression was significantly higher in squamous cell carcinoma patients (73.7%, 56/76) than in other-histology patients (P < .001). There was no significant correlation between maspin expression status and p-stage (Table 1Go).


Figure 1
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  		FIG. 1. IHS for maspin expression in NSCLC. (A) Strong expression in lung squamous cell carcinoma. (B) Strong expression in adenocarcinoma. Original magnification x100.

 
We further evaluated such biomarkers as IMVD, PI, AI, and p53 status in correlation with maspin expression. The incidence of aberrant p53 expression was significantly higher in maspin-strong tumors (56.2%) than in maspin-weak tumors (35.8%). There proved to be no significant correlation between ma-spin expression status and any other biomarker (Table 2Go).


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  		TABLE 2. Correlation between maspin expression and other biomarkers of tumor
 
Maspin Expression and Postoperative Survival
The 5-year survival rates of maspin-strong and maspin-weak patients were 68.7% and 65.2%, respectively, showing no significant difference according to maspin expression status for all patients (P = .528) (Table 3Go).


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  		TABLE 3. Maspin expression and postoperative survival in NSCLC
 
Subsequently, we conducted subset analyses on the prognostic significance of maspin status (Table 3Go). For squamous cell carcinoma patients, the 5-year survival rate of maspin-strong patients was 70.1%, which was significantly higher than that of maspin-weak patients (41.5%, P = .014) (Table 3Go, Fig. 2Go). For adenocarcinoma patients, there was no statistical difference in prognosis between maspin-strong and maspin-weak patients (5-year survival rates, 69.2% and 68.0%, respectively; P = .823). There proved to be no significant difference in prognosis according to maspin expression status in any p-stage subset of patients (Table 3Go).


Figure 2
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  		FIG. 2. Postoperative survival of patients with resected lung squamous cell carcinoma. Comparison of postoperative survival of maspin-high and maspin-low patients.

 
A multivariate analysis of prognostic factors was conducted in squamous cell carcinoma patients, which confirmed that strong expression of maspin was an independent and significant factor in predicting a favorable prognosis in this subset (hazard ratio = .475, 95% confidence interval [CI] .241–.936; P = .032) (Table 4Go).


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  		TABLE 4. Multivariate analysis of prognostic factors (Cox’s proportional hazards model) in lung squamous cell carcinoma
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, we demonstrated that enhanced maspin expression was a significant factor in predicting a favorable prognosis in resected lung squamous cell carcinoma, making this the first detailed study showing the prognostic significance of maspin expression status in correlation with other biomarkers. In oral squamous cell carcinoma, a clinical study also showed that high maspin expression was correlated with a favorable prognosis,23 which was consistent with results obtained in the present study. In contrast, most clinical studies on breast cancer have documented a poor prognosis in patients with enhanced maspin expression tumors.23 In NSCLC, only a few clinical studies on maspin expression have been reported.24,25 Nakashima and coworkers24 assessed maspin expression with IHS in lung adenocarcinoma and revealed that maspin-positive patients showed a somewhat better prognosis than maspin-negative patients (5-year survival rates, 62% and 42%, respectively), although the difference did not reach statistical significance (P = .11). In the present study, we documented similar postoperative survival rates in maspin-strong and maspin-weak adenocarcinoma patients (69.2% and 68.0% at 5 years, respectively; P = .823), which is different from the results of Nakashima and coworkers.24 Hirai and coworkers25 assessed maspin expression with IHS in all histological types of NSCLC and revealed that maspin expression is upregulated along with tumor progression, especially nodal involvement, and that maspin-positive patients showed a significantly poorer prognosis compared to maspin-negative patients, which entirely conflicts with the results of our study and the study by Nakashima and coworkers.24 Considering possible roles of maspin as a tumor suppressor, enhanced maspin expression might be correlated with inhibited tumor progression and prolonged survival. However, these conflicting results of maspin status as a prognostic factor in a variety of malignant tumors including NSCLC suggest that the clinical significance of maspin status remains controversial. In addition, we did not calculate disease-free survival in the present study because we could not determine the exact date of recurrence of all recurrent cases; disease-free survival according to maspin expression status was not documented in any other clinical study on NSCLC.24,25 In future large-scale prospective clinical studies, disease-free survival along with overall survival should be examined to assess the exact prognostic value of maspin expression status.

Along with the clinical significance of maspin expression status, detailed mechanism of maspin as a potential tumor suppressor should be revealed in experimental studies. Although some experimental studies have shown that maspin inhibits development and/or progression of malignant tumors through a p53-dependent pathway,26 inhibition of plasminogen activation,8 and angiogenesis inhibition,27 the exact biological mechanism of maspin remains unclear. In fact, we failed to show a significant correlation between maspin status and tumor angiogenesis, proliferative activity, or incidence of apoptosis. In the present study, we demonstrated a significant positive correlation only between enhanced maspin expression and aberrant expression of p53 that was frequently seen when the p53 gene was mutated. To the contrary, Machtens and coworkers28 showed that decreased maspin expression was correlated with positive p53 immunoreactivity in prostate cancer, which can be reasonably explained by an experimental result showing that wild-type p53 induces maspin gene expression through activation of the maspin promoter.26 Such a discrepancy may be caused by different biological implications of p53 accumulation among organs and/or by different types of p53 abnormality (aberrant protein accumulation or gene mutation), although the exact reasons remain unknown. Further clinical and experimental studies should be conducted to reveal an exact mechanism of maspin expression regulation by p53.

In addition, many experimental studies have revealed tumor-suppressor activities of maspin, but tumor-suppressor roles of maspin remain controversial in clinical studies. Some clinical studies have shown that enhanced maspin expression was correlated with tumor progression,29,30 whereas there was no difference in maspin expression according to p-stage and no correlation between the status of maspin expression and proliferative activity or incidence of apoptosis in the present study. Whether maspin expression is correlated with tumor progression or whether maspin acts as tumor suppressor should be prospectively examined in future clinical studies.

In the normal lung, some studies have shown cell type-specific and/or site-specific distribution of ma-spin expression as follows:17,18 (1) maspin expression was positive in basal cells of the bronchial epithelium and in myoepithelial cells of the bronchial glandular acini, (2) maspin expression was entirely negative in any peripheral lung cell (type I or II pneumocyte), and (3) maspin expression was gradually downregulated in the bronchiolar cells that connect the bronchus to the peripheral lung. These results may suggest that maspin expression is enhanced in the central airway and diminished in the peripheral lung, which may be inconsistent with our results showing that maspin expression was strong in squamous cell carcinoma that preferably developed in the central airway and reduced in adenocarcinoma that developed in the peripheral lung. In conclusion, enhanced expression of maspin, a potential tumor suppressor, was a significant factor in predicting a favorable prognosis in lung squamous cell carcinoma but not in lung adenocarcinoma.


   ACKNOWLEDGMENTS
 
We thank Ms. Seiko Sakai for assistance in preparation of the manuscript. This work was supported by grants-in-aid 17659429 (to F.T.) for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. This work was also supported by a grant from the Japanese Foundation for Multidisciplinary Treatment of Cancer.

Received for publication June 30, 2005. Accepted for publication May 2, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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