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Ann Thorac Surg 2005;79:990-995
© 2005 The Society of Thoracic Surgeons

Original article: General thoracic

Surgically Induced Accelerated Local and Distant Tumor Growth is Significantly Attenuated by Selective COX-2 Inhibition

Syed S.A. Qadri, FRCSIa, Jiang-Huai Wang, PhDb, John Calvin Coffey, AFRCSI, PhDa, Mahmood Alam, FRCSIa, Aonghus O’Donnell, FRCSIa, Thomas Aherne, FRCSIa, Henry P. Redmond, FRCSI, MCha,b,*

a Cork University Hospital, Wilton, Cork, Republic of Ireland
b University College Cork, Wilton, Cork, Republic of Ireland

Accepted for publication July 6, 2004.

* Address reprint requests to Professor Redmond, Department of Academic Surgery, Cork University Hospital, Wilton, Cork, Republic of Ireland (E-mail: redmondhp{at}shb.ie).

Presented at the Fortieth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 26–28, 2004.


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 
BACKGROUND: Even after apparently curative resection, lung cancer recurrence continues to lead to high mortality levels. The aim of this study was to assess the effects of cyclooxygenase-2 (COX-2) inhibitor on local and systemic recurrent tumor growth.

METHODS: C57BL/6 mice underwent mammary fat pad inoculation with 3LL cells. After two weeks growth, flank tumors were resected completely and followed for recurrent tumor growth. Postresection mice were randomized to receive placebo alone (group 1) or the selective COX-2 inhibitor, rofecoxib (group 2), daily for two weeks by tube feeding. Recurrent tumor growth kinetics were compared for both groups. Two weeks following primary tumor excision animals were sacrificed, after which lungs were resected and pulmonary metastatic burden was assessed using the lung-body weight ratio. Apoptotic and mitotic indices were established for recurrent tumors and lungs, using hematoxylin and eosin histology.

RESULTS: Two weeks postexcision of the primary tumor, recurrent tumors in the placebo group were significantly greater than the treatment group (p = 0.002). While primary tumors were typically encapsulated and not adherent, recurrent tumors in the placebo group were invasive, adherent to the chest wall and the overlying wound. In contrast, recurrent tumors in the treatment group were nonadherent to the chest wall. Moreover, postoperative pulmonary metastatic burden was significantly reduced in treated animals. Histologic examination revealed increased apoptosis as well as an increase in the apoptosis-mitosis ratio in treated animals.

CONCLUSIONS: Primary tumor excision was associated with accelerated local and systemic tumor recurrence. However, these effects were significantly attenuated using selective COX-2 inhibition. The COX-2-inhibition was associated with increased levels of apoptosis. These findings endorse a role for COX-2 inhibition in the secondary prevention of lung cancer recurrence at both local and systemic levels.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 
Despite the availability of numerous therapeutic modalities and extensive research, lung carcinoma remains a leading cause of mortality [1]. Even following curative-intent surgery for lung cancer, five year survival rates remain disappointingly low at 67% for stage IA, 57% for stage IB; 55% for stage IIA; 39% for stage IIB, and 23% for stage IIIA [2]. The Lung Cancer Study Group has reported that lung cancer local recurrence rates are 75% following limited resection. Such recurrences are associated with a 50% increase in mortality [3]. Even following complete excision of stage I lung cancer, five year recurrence rates are as high as 39% [4]. While most recurrences are systemic, local recurrence occurs in a significant proportion of patients [5]. Published studies have demonstrated that following that curative–intent therapy for non-small cell lung cancer (NSCLC) the rate of developing a metachronous primary is 1% to 2% per patient per year [6]. Saito and colleagues [7] demonstrated that the cumulative rate at 5 years, for metachronous tumors, was 11% and the incidence per patient-year of surveillance was 2.2%.

Numerous studies have shown that the process of tumor removal itself stimulates accelerated regrowth of minimal residual disease resulting in rapid cancer recurrence at local and systemic levels [8–12]. Nissen-Meyer and colleagues [13] have shown that early postoperative chemotherapy following mastectomy significantly reduced the recurrence and death rates. The Medical Research Council (MRC) OEO2 study has shown that preoperative chemotherapy improves overall and disease-free survival, when compared with surgical resection alone, in patients with resectable esophageal cancer [14]. The beneficial effects of preoperative and postoperative chemotherapy indicate that factors are present during the perioperative period which modifies the growth kinetic of minimal residual disease and that perioperative chemotherapy protects against these factors [15–17].

Enhanced expression of cyclooxygenase-2 (COX-2), but not COX-1, has been observed in tumor cells of various cancers including lung cancer. This property has been shown to have a negative prognostic impact in stage I lung cancers [18]. The COX-2 inhibitors have been shown to have antitumor effects, including increased apoptosis, antiangiogenesis, and immune restoration [19–22]. The effects of selective COX-2 inhibition have been assessed in a variety of experimental settings. However, we have found no studies to date which have evaluated their effects on the accelerated growth that minimal residual disease undergoes following primary tumor excision. To address this deficit, we have characterized the role of inhibiting COX-2 in two models of accelerated postoperative recurrent lung tumor growth. In the first, we assessed the role of selective COX-2 inhibition in accelerated local tumor recurrence. In the second, we characterized the role of selective COX-2 inhibition in protecting against accelerated metastatic tumor growth following primary tumor removal.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Discussion
 Acknowledgments
 References
 
Cell Line and Reagents
The murine Lewis Lung (3LL) carcinoma cell line was a generous gift from Dr Alan Alfieri (Albert Einstein College of Medicine, Department of Pathology, New York, NY). Cyclooxygenase-2 enzyme is overexpressed in these cells. Cells were grown in DMEM culture medium (Cell Culture Technologies, Zurich, Switzerland) supplemented with 10% fetal calf serum (FCS), penicillin (100 units/mL), streptomycin sulfate (100 µg/mL), and 2.0 mmol/L glutamine. Cells were maintained at 37°C in a humidified 5% CO2 atmosphere and subcultured by trypsinization with 0.05% trypsin-0.02% ethylenediaminetetraacetic acid when cells became confluent. Rofecoxib was purchased from Merck and Co (Whitehouse Station, NJ).

Animals and In Vivo Experiments
Six-week to 8-week-old C57BL/6 mice were used for all the experiments. These were treated in accordance with approved institutional protocols and following the guidelines of the department of health. Animals were bred in a standard laboratory and allowed free access to food and water in a temperature-controlled environment, with a 12 hours light and dark cycle. Age and weight matched mice were used throughout.

Inhibitor Experiments Evaluating the Effects of COX-2 Treatment on Local and Systemic Tumor Recurrence
The 3LL cells (0.5 x 105) suspended in 0.2 mL of PBS were injected in a mammary fat pad of C57BL/6 mice (n = 20, 10 per group) (Fig 1). Two weeks after inoculation, primary tumors were resected completely from all animals. Thereafter mice were randomized to receive placebo alone (group 1) or the selective COX-2 inhibitor, rofecoxib (group 2), daily for two weeks by tube feeding (gavage). The dose of rofecoxib given was 20 mg/kg body weight. Treatment was started after excising the primary tumor to determine the effect of COX-2 inhibitor on recurrence of tumor. After a further two weeks, all animals were sacrificed. Recurrent tumor and lungs were harvested. Tumor growth kinetics were compared for both groups. Pulmonary metastatic burden was assessed by counting macroscopic metastatic pulmonary nodules and histologic examination. This was further validated by comparing the lung-body weight ratios between groups. While the determinants of the lung-body weight ratio remains to be fully characterized, this ratio was taken as indicative only of pulmonary metastatic burden.



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  		Fig 1. Schematic diagram outlining experimental procedure: two weeks after inoculation, primary tumors were resected completely from all animals. Thereafter mice were randomized to receive placebo alone (group 1) or the selective cyclooxygenase-2 inhibitor rofecoxib (group 2), daily for two weeks by tube feeding. After a further two weeks, all animals were sacrificed. Recurrent tumors and lungs were harvested. (PBS = phosphate buffered saline.)

 
Tumor vascularity was recorded histologically, without the aid of immunoperoxidase stains, and evaluated at the base of the tumor, in the tumor periphery, within the tumor mass itself, and also by evaluating capillary tubule formation in peritumoral tissue. This technique has previously been validated by Kashani-Sabet and colleagues [23]. Tumor invasiveness was identified both macro and microscopically and defined by the involvement of locally adjacent structures such as chest wall and pleural involvement. Invasiveness was taken as implicit in the finding of metastases. All mice survived and completed the study.

Histopathological Analysis
All specimens were paraffin-embedded following fixation with 4% formaldehyde in phosphate-buffered saline. Tissue sections, 7 µm thick, were stained with hematoxylin and eosin. Apoptotic and mitotic cells were enumerated. Apoptotic and mitotic indices were established (mean numbers of apoptotic cells per 10 high power fields) for both recurrent tumors and lungs. All observation was performed by one observer who was blinded to the nature of the specimens. However, two independent observers evaluated all slides in a blinded fashion. The means documented were statically compared and if these were similar, an "overall mean" was generated. The data presented represent overall means.

Statistical Analysis
Results are presented as the mean ± standard deviation. Statistical analysis was performed using analysis of variance (ANOVA). Statistical significance was accepted at a p value less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Discussion
 Acknowledgments
 References
 
Selective COX-2 Inhibition Attenuates Surgically Induced Accelerated Local Recurrent Tumor Growth
At the time of primary tumor excision, primary tumor sizes were similar between test and control groups (1.53 ± 0.29 cm vs 1.36 ± 0.44 cm, p = 0.09). Primary and corresponding recurrent tumor growth rates were first compared. At two weeks postexcision of primary tumors, recurrent tumors in the placebo group were significantly greater in dimension compared with their corresponding primary tumors when the latter were excised (ie, 2.65 ± 0.74 cm vs 1.53 ± 0.29 cm [p = 0.001]) (Fig 2). Recurrent tumor volumes in the placebo group were significantly greater than that of corresponding primary tumor volumes, at the time of excision (ie, 5.84 ± 2.92 cm–3 vs 1.61 ± 0.63 cm–3 [p = 0.001]) (Table 1). Finally, primary and corresponding recurrent tumor volumes were compared for the COX-2 treatment group. At two weeks postprimary tumor excision, there were no significant differences in terms of size, volume, and weight between primary and corresponding recurrent tumors in animals that received the postoperative COX-2 inhibitor.



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  		Fig 2. Selective cyclooxygenase-2 inhibition attenuates surgically induced accelerated tumor growth. Decreased recurrent tumor growth in treated animal versus placebo group. Tumor growth was assessed as described above. Data are expressed as the mean ± standard deviation. The statistical significance of *p = 0.001 relates to primary versus recurrent tumors in placebo group and *p = 0.002 relates to recurrent tumors in treatment group versus placebo group. {diamondsuit} = placebo; • = treatment. (D = day.)

 

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  		Table 1. Size and Volume of the Recurrent Tumors Significantly Reduced by Rofecoxib
 
When recurrent tumors were compared between treatment and placebo groups, a significant reduction in volume was observed for the treatment group (1.22 ± 0.8 cm vs 2.65 ± 0.74 cm [p = 0.002] at 2 weeks) (Fig 2). As expected, recurrent tumor volumes in the COX-2 treated group were also significantly reduced relative to those of the placebo group (1.83 ± 1.87 cm–3 vs 5.84 ± 2.92 cm–3 [p = 0.002]). Similarly, recurrent tumor weights in the treatment group were significantly reduced relative to those of the placebo group (1.40 ± 1.72 gm vs 3.48 ± 2.08 gm [p = 0.004]) (Table 1).

Selective COX-2 Inhibition Attenuates Local Invasiveness and Pulmonary Metastatic Tumor Growth
Primary tumors were typically encapsulated and nonadherent. In contrast, recurrent tumors were both typically locally invasive (Table 2), being adherent to chest wall, musculature, and associated wound. These features were prominent for recurrent tumors in the placebo group. However, recurrent tumors in the treatment group were less aggressive, nonadherent, and often more localized.


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  		Table 2. Rofecoxib Reduced the Invasiveness and Rapid Growth of Both Local and Distal Recurrent Tumors
 
Postoperative pulmonary metastatic burden was significantly reduced in treated animals. In the treatment group, 3 of 10 mice developed macroscopic pulmonary metastatic nodules compared to 7 of 10 mice in the placebo group. Furthermore, nodules in the placebo group were overtly larger in volume, more scirrhous, bilateral, and multiple (93 nodules in 7 mice). In the treatment group, nodules were unilateral, small, and overall less in number (18 nodules in 3 mice). One mouse in the placebo group developed mediastinal metastasis while none occurred in the treatment group. Other locations like the brain or abdominal cavity were not investigated for the recurrence.

Recurrent tumors were characterized by lower and higher levels of apoptosis and mitosis, respectively. The apoptotic index and apoptosis-mitosis ratios were significantly reduced in recurrent tumors. However, these were significantly increased in the recurrent tumors of treated animals (0.96 ± 0.1 vs 0.68 ± 0.2, p = 0.02) (Fig 3). A similar pattern was observed in pulmonary metastatic nodules in treated and placebo groups; ie, pulmonary metastatic burden was significantly reduced in treated animals (0.86 ± 0.1 vs 0.65 ± 0.2). Moreover, the lung-body weight ratio of treated animals was significantly reduced relative to that seen in untreated animals.



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  		Fig 3. Reduced apoptosis in recurrent tumor reversed by rofecoxib treatment. Photomicrograph demonstrating (x10), (A) low levels of apoptosis in recurrent tumors in untreated animals (thick arrow = mitosis; thin arrows = apoptosis). (B) Increased apoptosis levels (arrows) in recurrent tumor of animals that received rofecoxib treatment.

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Discussion
 Acknowledgments
 References
 
Accumulating evidence supports a role for COX-2 inhibitors in the prevention of both primary and secondary cancer progression. Cyclooxygenase-2 enzyme is up-regulated in stromal and inflammatory cells by cytokines and other mediators and is expressed constitutively in many human cancers such as lung cancer. Several epidemiologic studies report that the inhibitors of cyclooxygenase enzyme, ie, aspirin and nonsteroidal antiinflammatory drugs, reduce the risk of colorectal, esophagus, stomach, prostate, breast, and lung cancer. This is reflected in experimental studies that demonstrate a similar benefit. Postulated mechanisms include promotion of tumor cell apoptosis and inhibition of angiogenesis [18–21]. The inhibition of COX-2 in colonic cancer has been shown to reduce the rate of tumor growth and metastasis both in vitro and in vivo [24]. Cyclooxygenase inhibitors are oncologically beneficial when used alone or in combination with other therapeutic modalities [25].

Studies have shown that removal of primary tumors adversely accelerates the subsequent growth of minimal residual disease leading to accelerated local recurrence [8–12]. In spite of curative-intent surgery for lung cancer, the incidence of recurrent lung cancer and metachronous lung cancer remain high [4, 7]. The MRC OEO2 study [14] and Nissen-Meyer and colleagues [13] have described increased survival and decreased recurrence and death rates in patients undergoing preoperative and postoperative chemotherapy. The latter findings indicate that factors are present during the perioperative period that are proneoplastic. Moreover, they indicate that a pharmacologic approach may be adopted in attenuating these potentially disastrous oncologic effects. Little is available in the literature regarding the effects of selective COX-2 inhibitors on lung cancer recurrence and, in particular, on surgically induced accelerated tumor growth at local and systemic levels.

We aimed to determine the effects of the highly selective COX-2 inhibitor, rofecoxib, on both local and systemic recurrent lung carcinoma. First we found that after complete excision of primary tumors, recurrent tumors in the placebo group grew to twofold the dimensions of primary tumors over the same duration. These findings support the previous suggestion that tumor removal alters the neoplastic properties of residual disease at both local and systemic levels [8]. However, rofecoxib treatment significantly reduced the rate at which recurrent tumors grew. While recurrent tumors in the placebo group exhibited a locally invasive phenotype this was far less prominent in animals that received postoperative rofecoxib. A similar pattern was observed at the systemic level. While primary tumor removal was associated with acceleration in spontaneous pulmonary metastasis formation, this was significantly attenuated in animals that received rofecoxib following primary tumor removal. The acceleration in local tumor growth that followed complete tumor removal was associated with a significantly reduced level of apoptosis. Treatment with rofecoxib led to a significant increase in apoptosis levels in both locally recurrent tumors as well as in metastases. These findings indicate that COX-2 inhibition, at least with rofecoxib, may protect against the acceleration in tumor growth that occurs at both local and systemic levels following primary tumor removal.

To summarize, recurrent tumors developed at an accelerated rate following excision of primary tumors. This was paralleled by increases in pulmonary metastasis following tumor removal. When rofecoxib was administered during the immediate postoperative phase, there were significant reductions in local recurrent tumor growth, as well as substantial reductions in spontaneous pulmonary metastasis formation. These findings point to a novel protective role for selective COX-2 antagonists following primary tumor excision. Moreover, they strengthen the suggestion that pharmacologic means may be instituted to protect patients against the potentially adverse effects of tumor removal.


   Discussion
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
Acknowledgments
 References
 
DR THOMAS A. D’AMICO (Durham, NC): That was very well presented. I have a question. I think, Dr Qadri, you have to acknowledge that the amount of immunosupression regime that occurs in humans that would induce accelerated tumor growth is probably less than what you would experience in your mouse model; at least I would hope so. How would you speculate the differential effect on the positive, the salutary effects of COX-2 inhibition in humans versus your mouse model, and how would you recommend that we test this?

DR QADRI: You are right. But immunosupression is not the only factor that helps in rapid growth of the recurrent tumors. There are multiple factors in the perioperative period. Manipulation of the tumor during the surgery is another factor. It has been shown that the primary tumors secrete two statin hormones; ie, angiostatin and endostatin, which depress the growth of secondary tumors, working as a negative feedback control. When the primary tumor is removed, that feedback control system is diminished, the secondary tumors start growing as well. The third factor is that surgery causes increased mitosis and decreased apoptosis in recurrent and other tumors. We have shown in another experiment that surgical excision of one tumor causes decreased apoptosis and increased mitosis in the other tumors at different places. COX inhibitors have been licensed to treat premalignant conditions of the colon; ie, familial adenomatous polyposis in the United States. Various studies have shown that they have encouraging effects in reducing the tumor growth in different cancers in vitro and in vivo. At present, different trials are running to determine the effects of COX-2 inhibitors in different premalignant and malignant conditions like in Barrett’s esophagus and colonic cancers. In our opinion it’s a promising drug to use as an adjunct therapy for the treatment of lung cancer.

DR JEFFREY PORT (New York, NY): I enjoyed your talk. Number one, are there any data on the COX-2 expression in these tumors? Number two, any idea if these results are as a result of COX-2 dependent or independent functions?

DR QADRI: We used Lewis lung cancer cells that have shown increased COX-2 expression. This cell line has been used in different studies and mentioned in multiple papers. You are right. COX-2 inhibitors work through both COX-2 dependent or independent pathways. We also have shown that COX-2 inhibitors affect not only through the COX-2-dependent pathway but also through the COX-2-independent pathway that we presented last year. We do not know exactly but it would be through both pathways.

DR MARGARET BLAIR MARSHALL (Philadelphia, PA): I have two questions. What dose of COX-2 inhibitor did you pick for your animals? How would you explain the difference between low and high dose nonselective COX-2 inhibitors in the New England Journal colon polyp trial?

DR QADRI: The dose of rofecoxib I used, was 20 mg/kg body weight that gives nearly similar serum levels of the clinically recommended dose of rofecoxib. I am sorry, what is your second question?

DR MARSHALL: How would you explain the differential effect between low dose and high dose nonselective COX-2 inhibitors?

DR QADRI: I don’t know why the high dose of COX-2 did not work, but we have done studies which have shown that a high dose of COX-2 inhibitors’ treatment not only inhibits the COX-2 enzymes, but it also inhibits the COX-1 enzymes. So a high dose of COX-2 inhibitors has not only an effect on the cancer cells but also has a damaging effect on normal endothelial cells. I think it needs further studies to confirm these effects of COX-2 inhibitors.

DR THOMAS K. WADDELL (Toronto, Ontario, Canada): Dr Qadri, you had one group which didn’t undergo resection of the primary tumor. Maybe you have done some prior studies and maybe I’m just ignorant in this field, but are there any data regarding the effect of COX-2 inhibition on that initial growth of the primary tumor?

DR QADRI: Yes. We have another study where we treated two groups with primary tumor growth. We injected the tumors in both groups and treated after one week and developed 0.5 to 1 mg size of the tumors; and we treated with COX-2 inhibitors by oral gavage and this significantly reduced the tumor growth on the primary side.

DR WADDELL: It did reduce?

DR QADRI: It did, yes.

DR WADDELL: So the COX-2 has an antitumor activity. It’s not particularly restricted just to this special model of postsurgical resection then.

DR QADRI: No. It has been shown to have antitumor activities on various models. This is the first time we used the COX-2 inhibitor on this new model of recurrent cancers. It has been tried in different cancers like colonic, breast, and lung cancers.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
References
 
We would like to thank Qiang Di Wu and Siobhan Blankson, and the staff of the biological services unit at the University College Cork for their technical support.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 

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