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Clinical Cancer Research Vol. 11, 1198-1202, February 2005
© 2005 American Association for Cancer Research

Imaging, Diagnosis, Prognosis

Expression of MDA-7/IL-24 and Its Clinical Significance in Resected Non–Small Cell Lung Cancer

Shinya Ishikawa1, Tatsuo Nakagawa1, Ryo Miyahara1, Yozo Kawano1, Kazumasa Takenaka1, Kazuhiro Yanagihara1,2, Yosuke Otake1,3, Hiromichi Katakura1, Hiromi Wada1 and Fumihiro Tanaka1

1 Department of Thoracic Surgery, Faculty of Medicine, Kyoto University; 2 Department of Translational Clinical Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; and 3 Department of Thoracic Surgery, Seishin-Iryo Center Hospital, Kobe, Japan

Requests for reprints: Fumihiro Tanaka, Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Shogoin-kawahara-cho 54, Sakyo-ku, Kyoto 606-8507, Japan. Phone: 75-751-4975; Fax: 75-751-4974; E-mail: ftanaka{at}kuhp.kyoto-u.ac.jp.


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: The melanoma differentiation-associated gene-7 (MDA-7) protein, also known as interleukin (IL)-24, is a novel candidate of tumor suppressor that can induce apoptosis experimentally in a variety of human malignant cells including lung cancer cells. However, only one clinical study has documented that MDA-7/IL-24 expression is down-regulated with progression of melanoma. Thus, the present study was conducted to assess the clinical significance of MDA-7/IL-24 expression in non–small cell lung cancer.

Experimental Design: A total of 183 consecutive patients with resected pathologic stage I-IIIA, non–small cell lung cancer were retrospectively reviewed, and immunohistochemical staining was used to detect MDA-7/IL-24 expression.

Results: MDA-7/IL-24 expression was high in 97 (53.0%) patients and low in the other patients. There was no significant correlation between MDA-7/IL-24 status and any patients' characteristic including pathologic stage. There was no significant difference in tumor angiogenesis or proliferative activity according to MDA-7/IL-24 status, but MDA-7/IL-24-high adenocarcinoma showed a significantly higher incidence of apoptotic tumor cell death than MDA-7/IL-24-low adenocarcinoma. MDA-7/IL-24-high patients seemed to show a favorable postoperative prognosis as compared with MDA-7/IL-24-low patients (5-year survival rates, 75.9% and 62.0%, respectively), although the difference did not reach a statistical significance (P = 0.061). Subset analyses showed that positive MDA-7/IL-24 expression was a significant factor to predict a favorable prognosis in adenocarcinoma (P = 0.033), which was confirmed by a multivariate analysis; there was no difference in the prognosis according to MDA-7/IL-24 status in squamous cell carcinoma.

Conclusions: MDA-7/IL-24 status was a significant prognostic factor in lung adenocarcinoma, not in lung squamous cell carcinoma.

Key Words: Melanoma differentiation associated gene-7 • MDA-7 • IL-24 • Lung cancer • Surgery • Prognosis


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Primary lung cancer is the leading cause of cancer death with a poor prognosis in most industrialized countries, and non–small cell lung cancer (NSCLC) account for ~80% of primary lung cancer (1). Surgery is the most effective therapeutic modality for NSCLC patients, but the postoperative prognosis is not satisfactory (2, 3). To improve the prognosis, it is important to establish biological markers other than tumor-node-metastasis factors that determine prognosis and response to a particular treatment. Although many possible biological markers have been reported, none of them has been established as a marker in decision-making of the treatment of NSCLC (4). In addition, chemotherapy and/or radiotherapy may be given for unresectable NSCLC patients, but the survival benefit remains minimal. Thus, novel strategies for the treatment of NSCLC should be developed (5).

The melanoma differentiation-associated gene-7 (MDA-7) protein, recently named as interleukin (IL)-24, is a novel member of the IL-10 family of cytokines (6). The MDA-7/IL-24 gene was originally identified by subtraction hybridization in the context of induction of growth arrest and differentiation of melanoma cells (6, 7). Experimental studies have revealed that induction of the MDA-7/IL-24 gene suppressed growth in a wide variety of cancer cell lines including NSCLC cell lines with minimal toxicity to normal cells (8–13). These results strongly suggest that the MDA-7/IL-24 gene is a novel tumor suppressor gene and can be a novel target of cancer therapy. However, only one clinical study has documented a clinical significance of MDA-7/IL-24 expression in which MDA-7/IL-24 expression is down-regulated with progression of melanoma (14); no clinical study has been reported in other malignant tumors including NSCLC. Thus, we assessed in the present study a clinical significance of MDA-7/IL-24 expression, especially the prognostic significance, in resected NSCLC. In addition, a recent experimental study has revealed that MDA-7/IL-24 can suppress tumor progression through inhibition of tumor angiogenesis (15), and we also examined in the present study a correlation between MDA-7/IL-24 expression and intratumoral microvessel density that is a measurement of tumor angiogenesis.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients. We retrospectively reviewed a total of 185 consecutive patients with pathologic (p)-stage I-IIIA NSCLC who underwent complete tumor resection and nodal dissection without any preoperative therapy at the Department of Thoracic Surgery, Kyoto University between January 1, 1985 and December 31, 1990. P-stage was reevaluated and determined according to the current tumor-node-metastasis classification as revised in 1997 (1). Histologic type was also redetermined according to the classification by the WHO as revised in 1999 (16). Two patients who experienced operation-related death were excluded from the study. Thus, a total of 183 patients were finally evaluated in the present study. For all these patients, the inpatient medical records, chest X-ray films, whole-body computed tomography films, bone and gallium scanning data, and records of surgery were reviewed without knowledge of the results of immunohistochemical staining or the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining.

Details of postoperative adjuvant therapy were described in previous studies (17, 18). In brief, cisplatin-based chemotherapy, radiation, and oral administration of tegafur (a fluorouracil derivative drug) were prescribed postoperatively for 46, 28, and 52 patients, respectively. Intraoperative therapy was not done on any patient.

The day of thoracotomy was considered the starting day for counting postoperative survival days. The mean follow-up was 1898 days (range, 48-5,181 days). This study has been approved by the Ethics Committee of Faculty of Medicine, Kyoto University.

Tissue Preparation. All tumor specimens were fixed immediately in 10% (v/v) formalin, and then embedded in paraffin. Serial 4-µm sections were prepared from each sample and used for routine H&E staining, the TUNEL staining to detect apoptotic cells, and immunohistochemical staining to determine MDA-7/IL-24 expression status, intratumoral microvessel density, and proliferative index.

Immunohistochemistry. A horseradish peroxidase-streptavidin complex kit (ImmunoCruz Staining System, Santa Cruz Biotechnology, Inc., Santa Cruz, CA) was used; the primary antibody used for detection of MDA-7/IL-24 was a goat polyclonal antibody (sc-12408, Santa Cruz Biotechnology). Dewaxed sections were incubated overnight with the primary antibody diluted at 1:100, and then sections were incubated for 30 minutes with the secondary antibody followed by a 30-minute incubation with the horseradish peroxidase-streptavidin complex reagent. The immunolabeling was developed with the chromogen, 3,3'-diaminobenzidine tetrahydrochloride. Hematoxylin was applied as a counter stain. For negative control, goat immunoglobulin G was used instead of the primary antibody. Normal skin section (DAKO Japan, Kyoto, Japan) was served as a positive control slide.

The staining intensity of MDA-7/IL-24 in tumor cells was graded as follows: 0, negative; 1, weak staining; 2, strong staining comparable to that seen in a positive control slide (normal skin); 3, very strong staining. The proportion of positive-staining tumor cell was also graded according to the percentage as follows: 0, none; 1, 1% to 50%; 2, 50% to 100%. The staining intensity score was multiplied by score of positively stained cells to obtain the overall score. Slides with an overall score of 0 to 1 were regarded as MDA-7/IL-24-low, and those with an overall score of 2 to 6 as MDA-7/IL-24-high. Slides were evaluated by two authors independently (S.I. and T.N.) without knowledge of any patients' clinicopathologic feature. A different evaluation of MDA-7/IL-24 expression by the two authors was made in 27 patients (11.6%), and the slides were reevaluated until the evaluations coincided. In case of a discordant evaluation after reevaluation, the slides were evaluated by another author (F.T.).

Proliferative index and intratumoral microvessel density were also determined with immunohistochemical staining as described previously (17, 19, 20). Briefly, an anti–proliferating cell nuclear antigen monoclonal antibody [PC-10, mouse immunogloblin G2a, {kappa}; DAKO Japan] diluted at 1:50 was used as the primary antibody to determine proliferative index (17, 19); proliferative index was defined as the percentage of proliferating cell nuclear antigen–positive staining tumor cells. Intratumoral microvessel density was determined with an anti-CD34 monoclonal antibody QBEnd10 (mouse immunogloblin G1, {kappa}; DAKO Japan) diluted at 1:50; the 10 most vascular areas within a section were selected for evaluation of angiogenesis, and the average counts of CD34-positive vessels were recorded as intratumoral microvessel density in each case (20).

Detection of Apoptosis. The TUNEL staining was done using the In situ Death Detection Kit, POD (Boehringer Mannheim, Mannheim, Germany) following the protocol of the manufacturer as described previously (17). The specificity of the TUNEL staining of apoptotic cells was confirmed by making the negative and the 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 0.7 mg/mL DNase I (Stratagene, La Jolla, CA) before the TUNEL reaction. Apoptotic cells were determined with careful observation of TUNEL-staining sections and serial H&E-staining sections, and TUNEL-positive staining cells, if they did represent the histologic features of necrosis in H&E-staining sections, were not considered to be apoptotic cells. In each case, a total of 10,000 tumor cells, consisting of 1,000 tumor cells each in 10 different fields, were evaluated at high magnification (x400) by two authors (F.T. and Y.O.) independently. The apoptotic index was defined as the number of apoptotic cells per 1,000 tumor cells.

Statistical Analysis. Counts were compared by the {chi}2 test. Continuous data were compared using the Student's t test if the distribution of the samples was normal or using 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 the survival rates were assessed by the Wilcoxin test. Death of any cause was included in calculation of postoperative survival. Multivariate analysis of the prognostic factors was done using Cox's proportional hazard model. Differences were considered significant when P < 0.05. All statistical manipulations were done using the SPSS version 10 for the Windows software system (SPSS, Inc., Chicago, IL).


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Expression of MDA-7/IL-24 in Non–Small Cell Lung Cancer. Positive staining was observed in the cytoplasm of tumor cells (Fig. 1A and B). Expression of MDA-7/IL-24 was high in 97 patients (53.0%) and low in the other 86 patients. There was no significant correlation between MDA-7/IL-24 expression status and any patients' characteristic (Table 1).



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  		Fig. 1 MDA-7/IL-24 expression in lung squamous cell carcinoma (A) and adenocarcinoma (B).

 

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  		Table 1 Characteristics of patients and MDA-7/IL-24 expressions

 
The mean intratumoral microvessel densities for MDA-7/IL-24-high tumor and for MDA-7/IL-24-low tumor were 181.9 and 169.8, respectively, showing no significant difference (P = 0.391; Table 2). For all patients, there was no significant difference in the mean proliferative index or in the mean apoptotic index according to the status of MDA-7/IL-24 expression; for adenocarcinoma patients, however, the mean apoptotic index for MDA-7/IL-24-high tumor was significantly higher than that for MDA-7/IL-24-low tumor (Table 2).


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  		Table 2 Correlation between MDA-7/IL-24 expression and other biomarkers of tumor

 
Expression of MDA-7/IL-24 and Postoperative Survival. For all 183 patients, 5-year survival rates of MDA-7/IL-24-high patients and MDA-7/IL-24-low patients were 74.6% and 62.0%, respectively; MDA-7/IL-24-high patients seemed to show a marginally favorable postoperative prognosis, although the difference did not reach a statistical significance (P = 0.061; Table 3 and Fig. 2A).


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  		Table 3 MDA-7/IL-24 expression and postoperative survival in NSCLC

 


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  		Fig. 2 A and B, postoperative survival of patients with completely resected p-stage I-IIIA NSCLC. Comparison of postoperative survival according to MDA-7/IL-24 expression.

 
Subset analyses revealed that high expression of MDA-7/IL-24 was a significant factor to predict a favorable prognosis in adenocarcinoma patients (P = 0.033; Table 3 and Fig. 2B). A multivariate analysis of prognosis factors using a Cox proportional hazard model confirmed that high MDA-7/IL-24 expression was an independent and significant factor to predict a favorable prognosis in lung adenocarcinoma (Table 4).


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  		Table 4 Multivariate analysis of prognostic factors (Cox's proportional hazard model) in lung adenocarcinoma

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The present study for the first time assessed the clinical significance of MDA-7/IL-24 expression in NSCLC, and revealed that high MDA-7/IL-24 expression was a significant factor to predict a favorable postoperative prognosis in lung adenocarcinoma. In contrast to adenocarcinoma patients, squamous cell patients showed a similar postoperative survival regardless of MDA-7/IL-24 expression status in the present study. In accordance of a previous clinical study (14), diffuse cytoplasmic immunostaining was observed in most MDA-7 /IL-24 expression-positive cases, and we could not assess the MDA-7/IL-24 status by classification according to the staining pattern. There has been only one clinical study on MDA-7/IL-24 expression (14), which showed down-regulation of MDA-7 /IL-24 expression with progression of melanoma, but did not assess the prognostic significance. These results strongly suggest that MDA-7/IL-24 can be a new prognostic marker in lung adenocarcinoma, which should be confirmed in future prospective studies.

The present study failed to show a significant difference in the mean intratumoral microvessel density according to the status of MDA-7/IL-24 expression, although the mean intratumoral microvessel density for MDA-7/IL-24-high tumor seemed to be somewhat lower than that for MDA-7/IL-24-low tumor (169.8 versus 181.9). These results may not be consistent with experimental results showing that a secreted form of MDA-7/IL-24 (sMDA-7/IL-24) shows an anti-angiogenic activity (15). In the present study, we examined the status of MDA-7/IL-24 expressed on tumor cells, and could not assess the status of sMDA-7/IL-24. To clarify the anti-angiogenic effect of sMDA-7/IL-24 in clinical materials, sMDA-7/IL-24 should be examined in future clinical studies in correlation with tumor angiogenesis.

We showed in the present study that the mean apoptotic index for MDA-7/IL-24-high tumor was significantly higher than that for MDA-7/IL-24-low tumor in lung adenocarcinoma. Increased apoptotic tumor-cell death in lung adenocarcinoma might be a reason for a significantly favorable postoperative prognosis in MDA-7/IL-24-high patients. Recent experimental studies have also shown that MDA-7/IL-24 can induce tumor-cell specific apoptotic cell death through both secretory and non-secretory pathways (15, 21), although the exact roles of MDA-7/IL-24 in induction of apoptosis remain unclear. Further experimental and clinical studies should be conducted to reveal the exact MDA-7/IL-24 induced apoptotic tumor-cell death.

We showed no difference in MDA-7/IL-24 expression according to p-stage, which was not consistent with results documented in experimental studies (8–13, 15, 21) or in a clinical study (14). Many experimental studies have shown that MDA-7/IL-24 can suppress tumor growth; for example, ectopic expression of MDA-7/IL-24 induces growth arrest and apoptosis in a variety of malignant tumors including breast, lung, colon, cervical, prostate, and pancreatic cancer as well as melanoma (8–13). One reason for the discrepancy between these experimental studies and the present study might be insufficient number and/or heterogeneity (histology and differentiation of tumor cells) of patients reviewed in the present study. In a clinical study in which immunohistochemical staining was used to detect expression of MDA-7/IL-24 expression (14), MDA-7/IL-24 expression was down-regulated with progression of melanoma. We cannot address a reason for the discrepancy, and the correlation between MDA-7/IL-24 status and tumor progression in malignant tumors including NSCLC should be examined in future large-scale clinical studies. In conclusion, high expression of MDA-7/IL-24 was a significant factor to predict a favorable prognosis in lung adenocarcinoma. These results suggest that MDA-7/IL-24 may be a new prognostic marker in NSCLC.


   FOOTNOTES
 
Grant support: Grants-in-Aid 14370410 (to F.T.) and 15390411 (to W.H. and F.T.) for Scientific Research (B) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; and The Japanese Foundation for Multidisciplinary Treatment of Cancer.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 8/26/04; revised 10/19/04; accepted 11/ 4/04.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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