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Clinical Cancer Research Vol. 5, 1001-1005, May 1999
© 1999 American Association for Cancer Research

Advances in Brief

Prognostic Significance of Elevated Cyclooxygenase 2 Expression in Primary, Resected Lung Adenocarcinomas1

Hiroyuki Achiwa, Yasushi Yatabe, Toyoaki Hida2, Tetsuo Kuroishi, Ken-ichi Kozaki, Shigeo Nakamura, Makoto Ogawa, Takahiko Sugiura, Tetsuya Mitsudomi and Takashi Takahashir

Departments of Internal Medicine [H. A., T. H., M. O., T. S.], Pathology and Clinical Laboratories [Y. Y., S. N.], and Thoracic Surgery [T. M.], Aichi Cancer Center Hospital; and Laboratory of Epidemiology [T. K.], Pathophysiology Unit [K-i. K., T. T.], and Laboratory of Ultrastructure Research [T. T.], Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Recently, we demonstrated that elevated expression of cyclooxygenase 2 (COX-2) is frequently seen in a specific type of lung cancer, i.e., adenocarcinoma, and is possibly associated with its invasion and metastasis. Here, the prognostic significance of elevated COX-2 expression was evaluated in a cohort of 130 adenocarcinoma patients who had consecutively undergone potentially curative resections. Immunohistological examination showed the presence of tumor cells with markedly increased COX-2 immunoreactivity in 93 of 130 (72%) cases. No relationship was found between the increase in COX-2 expression and clinical outcomes when the entire cohort was considered (P = 0.099). Reasoning that the influence of the increase in COX-2 expression may have been obscured by the clinical and molecular pathogenetic complexities in cases with an advanced disease, we also separately analyzed the prognostic significance of increased COX-2 expression after stratification according to the disease stage. A significant relationship between elevated COX-2 expression and shortened patient survival was observed only in a cohort of patients with stage I disease (P = 0.034). These findings suggest that an increase in COX-2 expression may be clinically significant for the prognosis of patients undergoing surgical resection of early-stage adenocarcinomas and, thus, warrant further conclusive studies involving a larger cohort.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Lung cancer currently claims more than 40,000 lives annually and is expected to become the leading cause of cancer deaths in Japan in the very near future (1) . Although surgical resection can provide lung cancer patients with the hope of a cure, the long-term survival rate, even in surgically treated cases, remains unsatisfactory. Identification of genetic markers associated with a distinct prognostic outcome would, therefore, be useful for defining a subset of lung cancer patients as candidates for new investigational adjuvant therapies, leading to an improvement in prognosis.

Recent studies have suggested that an increase in the expression of COX-2,3 a key inducible enzyme involved in the production of prostaglandins and other eicosanoids, may play a significant role in carcinogenesis in addition to its well-known role in inflammatory reactions (2, 3, 4, 5, 6, 7, 8, 9, 10, 11) . Oshima et al. (8) recently provided direct genetic evidence that formation of intestinal polyps in Apc{Delta}716 knockout mice was dramatically suppressed by crossing with COX-2 knockout mice, indicating that induction of COX-2 represents an early rate-limiting step. Moreover, a number of clinical and epidemiological studies suggest that nonsteroidal anti-inflammatory drugs induce a significant and often complete regression of colonic polyps in patients with familial adenomatous polyposis and also reduce the risk of colon cancer in nonfamilial adenomatous polyposis subjects (12, 13, 14, 15, 16, 17) . Although previous studies have been largely confined to colorectal tumorigenesis, we and another group recently reported that an increased expression of COX-2 is also frequently seen in a specific type of lung cancer, i.e., adenocarcinoma (18 , 19) and is possibly associated with its invasion and metastases (18) .

This study was conducted to evaluate the prognostic significance of an increase in COX-2 expression in a cohort of 130 adenocarcinoma patients who had consecutively undergone potentially curative resections between January 1986 and December 1990.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Patients and Tissue Samples.
Between January 1986 and December 1990, 131 adenocarcinoma cases successfully underwent potentially curative operations at Aichi Cancer Center Hospital (Nagoya, Japan) and were considered appropriate for inclusion in this study, which was designed to evaluate the prognostic significance of elevated COX-2 expression in surgically treated patients with adenocarcinoma. Exclusion of one case (0.8%) because of a lack of adequate pathology specimens yielded a cohort of 130 patients who were fully assessable for increased COX-2 expression. Complete clinical and follow-up information was available for all 130 patients, with a median follow-up duration of 85 months (range, 2–144 months). Histological classification was performed according to the criteria of the WHO, and postoperative pathological staging was performed according to those of the international staging system for lung cancer (20 , 21) .

Immunohistochemistry.
Four-µm-thick formalin-fixed and paraffin-embedded tissue sample sections were deparaffinized in xylene, treated with 0.3% hydrogen peroxide in methanol for 20 min to block endogenous peroxidase activity, microwaved in citrate-phosphate buffer (pH 6.0) for antigen retrieval, and incubated with 10% normal goat serum for 30 min to block nonspecific binding. Rabbit polyclonal antibody specific for human COX-2 (Immuno-Biological Laboratories Co., Ltd., Gunma, Japan) was then applied as the primary antibody at a dilution of 1:25 at 4°C overnight, followed by a standard staining procedure using the Vectastain ABC kit (Vector Laboratories, Burlingame, CA). Nonimmunized rabbit serum was used for the negative control.

Evaluation of COX-2 Immunostaining.
The results were evaluated independently by three observers (H. A., Y. Y., and T. H.) and repeated three times each. In cases of occasional discrepancy in the interpretation, consensus was achieved after discussion of findings obtained with the aid of a multiheaded microscope. Reactions in smooth muscles and vascular endothelial cells, which were present in all specimens, were used as internal built-in controls, and cases with tumor cells showing significantly more intense staining than the internal control cells were recorded as positive.

Statistical Analysis.
All statistical analyses were carried out with the Statistical Analysis System software (Version 6.12, SAS Institute Inc., Cary, NC) after completion of the immunohistological evaluation. The {chi}2 test was used to examine the association between increased COX-2 expression and various clinicopathological characteristics. The Kaplan-Meier method was used to estimate survival as a function of time, and survival differences were analyzed with the log-rank test. Cox proportional hazards modeling of factors potentially related to survival was performed to identify which independent factors might jointly have a significant influence on survival.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Relationship between the Expression Status of COX-2 and Clinicopathological Characteristics.
Of the 130 patients, 93 (72%) exhibited markedly more intense COX-2 immunoreactivities in tumor cells than in the internal control cells, whereas the remaining 37 cases did not show such an increase in COX-2 expression (Fig. 1)Citation . There was no significant association between elevated COX-2 expression and various clinicopathological features, including age (P = 0.207), sex (P = 0.560), tumor size (P = 0.310), nodal involvement (P = 0.853), disease stage (P = 0.983), and smoking history (P = 0.453; Table 1Citation ).



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  		Fig. 1. Representative results of immunohistochemical staining of COX-2. A, a representative case with elevated COX-2 expression. B, a representative case without an increase in COX-2 expression.

 

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  		Table 1 Relationships between elevated COX-2 expression and clinical characteristics

 
Relationship between COX-2 Expression and Survival.
Kaplan-Meier survival curves demonstrated no association between increased COX-2 expression and a poor prognosis when the entire cohort was considered (P = 0.099 by log-rank test; Fig. 2ACitation ). We also analyzed the prognostic significance of an increase in COX-2 expression after stratification according to the disease stage, reasoning that the influence of elevated COX-2 expression may have been obscured by the clinical and molecular pathogenetic complexities in cases with an advanced disease. Kaplan-Meier survival curves showed that stage I patients without an increase in COX-2 expression had a 88% 5-year survival rate, in contrast to the 66% of those with such an increase. Furthermore, a statistically significant survival difference was observed in patients with stage I disease between those with and without an increase in COX-2 expression (P = 0.034 by log-rank test; Fig. 2BCitation ). In contrast, there was no such difference in patients with stage II/III disease (P = 0.709 by log-rank test; Fig. 2CCitation ). These findings suggest that the absence of an increase in COX-2 expression may be indicative of a better prognosis.



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  		Fig. 2. Survival curves according to the presence or absence of increased COX-2 expression for the entire cohort (A) as well as for patients with stage I (B) or stage II/III (C) disease.

 
We further carried out multivariate analysis to identify which independent factors would jointly have a significant influence on the survival of patients with stage I disease. Using age, sex, tumor size, smoking history and COX-2 expression as variables showed that, in addition to the significant effect of primary tumor size [hazard ratio (pT2/pT1) = 2.982; 95% confidence interval, 1.374–6.475; P = 0.057), there was a trend toward poorer prognosis in patients with elevated COX-2 expression (hazard ratio (positive/negative) = 2.500; 95% confidence interval, 0.945–6.610; P = 0.0648; Table 2Citation ).


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  		Table 2 Cox proportional hazards model for various potential prognostic factors of patients with stage I disease of adenocarcinoma of the lung

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
We previously showed frequent occurrence of increased COX-2 expression specifically in adenocarcinomas and the presence of significantly more intense COX-2 immunoreactivity in tumor-invasive lesions and in lymph node metastases (18) . Here, therefore, we investigated 130 patients with adenocarcinomas who underwent consecutive surgical resections to determine whether an increase in COX-2 expression could have prognostic significance. A correlation between 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, possibly reflecting the clinical and molecular pathogenetic complexities of the latter. In this regard, it is noteworthy that a similar difference between these two subgroups of adenocarcinoma cases was observed in our previous study on the prognostic significance of p53 abnormalities (22) . This is, to our knowledge, the first demonstration of the possibility of the prognostic significance of COX-2 expression not only in lung cancers but also in other types of human cancers.

In addition to our previous demonstration of the possible involvement of COX-2 in lung cancers (18) , there are several lines of experimental evidence supporting such involvement in the process of tumor progression. For example, overexpression of COX-2 reportedly suppresses apoptosis, resulting in the enhanced tumorigenic potential of rat intestinal epithelial cells (9) , whereas COX-2 has been found to possibly play a role in inducing more potent invasiveness of colon cancer cells in vitro (10) and in the chemotactic response of vascular endothelial cells (11) . Although further in vitro and also animal model studies of lung carcinogenesis and tumor progression are required to examine whether COX-2 is, indeed, the responsible molecule, the availability of COX-2 inhibitors, or nonsteroidal anti-inflammatory drugs, makes these results more interesting than those of previous studies on other prognostic factors because increased COX-2 expression might represent a direct therapeutic target in such cases with an unfavorable prognosis. The potential use of COX-2 inhibitors in adjuvant setting in early-stage adenocarcinoma cases may be of special interest considering their much less adverse effects than conventional cytotoxic anticancer agents. In this regard, it is interesting that in a preliminary study of ours COX-2-specific inhibitors were found to elicit apoptosis in lung cancer cell lines in vitro.4

These findings of the prognostic significance of an increase in COX-2 expression in stage I patients were obtained by analysis of a relatively large number of consecutively operated cases and, thus, should be of considerable clinical interest. However, these findings need to be confirmed with larger independent groups of patients because careful interpretation of findings based on subset analyses is particularly important in avoiding the attachment of significance to results by chance alone. In conjunction with the recent development of potent COX-2-specific inhibitors (23) , further studies are warranted to gain more insight into the biological roles of COX-2 in the development and progression of adenocarcinoma of the lung. Such insight would be especially significant for future clinical applications, which may ultimately lead to a reduction in the high death toll caused by this fatal disease.


   ACKNOWLEDGMENTS
 
We thank H. Ishida for his technical assistance and G. Giacconne for his helpful discussion.


   FOOTNOTES
 
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.

1 This work was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare of Japan, a grant from the Smoking Research Foundation, and a Grant for Biomedical Research from Bristol Myers Squibb. Back

2 To whom requests for reprints should be addressed, at Department of Internal Medicine, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. Back

3 The abbreviation used is: COX-2, cyclooxygenase 2. Back

4 Unpublished observations. Back

Received 12/16/98; revised 2/16/99; accepted 2/17/99.


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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
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S. A. Khuder, N. A. Herial, A. B. Mutgi, and D. J. Federman
Nonsteroidal Antiinflammatory Drug Use and Lung Cancer: A Metaanalysis
Chest, March 1, 2005; 127(3): 748 - 754.
[Abstract] [Full Text] [PDF]

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 CarcinogenesisHome page
Y. Ding, M. Tong, S. Liu, J. A. Moscow, and H.-H. Tai
NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH) behaves as a tumor suppressor in lung cancer
Carcinogenesis, January 1, 2005; 26(1): 65 - 72.
[Abstract] [Full Text] [PDF]

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 CarcinogenesisHome page
S. A. Blaine, A. M. Meyer, G. Hurteau, M. Wick, J. A. Hankin, R. C. Murphy, A. J. Dannenberg, M. W. Geraci, K. Subbaramaiah, and R. A. Nemenoff
Targeted over-expression of mPGES-1 and elevated PGE2 production is not sufficient for lung tumorigenesis in mice
Carcinogenesis, January 1, 2005; 26(1): 209 - 217.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
L. T. Soumaoro, H. Uetake, T. Higuchi, Y. Takagi, M. Enomoto, and K. Sugihara
Cyclooxygenase-2 Expression: A Significant Prognostic Indicator for Patients With Colorectal Cancer
Clin. Cancer Res., December 15, 2004; 10(24): 8465 - 8471.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
J. R. Brown and R. N. DuBois
Cyclooxygenase as a Target in Lung Cancer
Clin. Cancer Res., June 15, 2004; 10(12): 4266S - 4269S.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
H. E. Zeytin, A. C. Patel, C. J. Rogers, D. Canter, S. D. Hursting, J. Schlom, and J. W. Greiner
Combination of a Poxvirus-Based Vaccine with a Cyclooxygenase-2 Inhibitor (Celecoxib) Elicits Antitumor Immunity and Long-Term Survival in CEA.Tg/MIN Mice
Cancer Res., May 15, 2004; 64(10): 3668 - 3678.
[Abstract] [Full Text] [PDF]

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 ChestHome page
J. R. Brown and R. N. DuBois
Cyclooxygenase-2 in Lung Carcinogenesis and Chemoprevention: Roger S. Mitchell Lecture
Chest, May 1, 2004; 125(5_suppl): 134S - 140S.
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 Cancer Res.Home page
D. Wei, L. Wang, Y. He, H. Q. Xiong, J. L. Abbruzzese, and K. Xie
Celecoxib Inhibits Vascular Endothelial Growth Factor Expression in and Reduces Angiogenesis and Metastasis of Human Pancreatic Cancer via Suppression of Sp1 Transcription Factor Activity
Cancer Res., March 15, 2004; 64(6): 2030 - 2038.
[Abstract] [Full Text] [PDF]

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 JCOHome page
H. Endoh, S. Tomida, Y. Yatabe, H. Konishi, H. Osada, K. Tajima, H. Kuwano, T. Takahashi, and T. Mitsudomi
Prognostic Model of Pulmonary Adenocarcinoma by Expression Profiling of Eight Genes As Determined by Quantitative Real-Time Reverse Transcriptase Polymerase Chain Reaction
J. Clin. Oncol., March 1, 2004; 22(5): 811 - 819.
[Abstract] [Full Text] [PDF]

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 FASEB J.Home page
T. KUWANO, S. NAKAO, H. YAMAMOTO, M. TSUNEYOSHI, T. YAMAMOTO, M. KUWANO, and M. ONO
Cyclooxygenase 2 is a key enzyme for inflammatory cytokine-induced angiogenesis
FASEB J, February 1, 2004; 18(2): 300 - 310.
[Abstract] [Full Text] [PDF]

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 CarcinogenesisHome page
D. Campa, S. Zienolddiny, V. Maggini, V. Skaug, A. Haugen, and F. Canzian
Association of a common polymorphism in the cyclooxygenase 2 gene with risk of non-small cell lung cancer
Carcinogenesis, February 1, 2004; 25(2): 229 - 235.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
D. Saha, K. R. Sekhar, C. Cao, J. D. Morrow, H. Choy, and M. L. Freeman
The Antiangiogenic Agent SU5416 Down-Regulates Phorbol Ester-Mediated Induction of Cyclooxygenase 2 Expression by Inhibiting Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activity
Cancer Res., October 15, 2003; 63(20): 6920 - 6927.
[Abstract] [Full Text] [PDF]

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 Ann. Thorac. Surg.Home page
J. E. Castelao, R. D. Bart III, C. A. DiPerna, E. M. Sievers, and R. M. Bremner
Lung cancer and cyclooxygenase-2
Ann. Thorac. Surg., October 1, 2003; 76(4): 1327 - 1335.
[Abstract] [Full Text] [PDF]

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 JNCI J Natl Cancer InstHome page
H. Choy and L. Milas
Enhancing Radiotherapy With Cyclooxygenase-2 Enzyme Inhibitors: A Rational Advance?
J Natl Cancer Inst, October 1, 2003; 95(19): 1440 - 1452.
[Abstract] [Full Text] [PDF]

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 J. Thorac. Cardiovasc. Surg.Home page
C. A. DiPerna, R. D. Bart, E. M. Sievers, Y. Ma, V. A. Starnes, and R. M. Bremner
Cyclooxygenase-2 inhibition decreases primary and metastatic tumor burden in a murine model of orthotopic lung adenocarcinoma
J. Thorac. Cardiovasc. Surg., October 1, 2003; 126(4): 1129 - 1133.
[Abstract] [Full Text] [PDF]