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Right arrow Lung - cancer

Ann Thorac Surg 2003;76:1327-1335
© 2003 The Society of Thoracic Surgeons

Review

Lung cancer and cyclooxygenase-2

J. Esteban Castelao, MD, PhDa, Robert D. Bart, III, MDb,c,d, Costanzo A. DiPerna, MDd, Eric M. Sievers, MDd, Ross M. Bremner, MD, PhDd*

a Department of Preventive Medicine, Norris Comprehensive Cancer Center, Los Angeles, CA, USA
b Department of Pediatrics, Los Angeles, CA, USA
c Department of Cell and Neurobiology, Los Angeles, CA, USA
d Department of Cardiothoracic Surgery, Hastings Thoracic Oncology Laboratory, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA

* Address reprint requests to Dr Bremner, Department of Cardiothoracic Surgery, Keck School of Medicine of the University of Southern California, 1510 San Pablo St, Suite 415, Los Angeles, CA 90033, USA
e-mail: rbremner{at}surgery.usc.edu


   Abstract
Top
 Abstract
Introduction
 Lung cancer and COX-2
 Tumorigenesis of COX-2
 Conclusions
 Acknowledgments
 References
 
Lung cancer is by far the leading cause of cancer-related death. Overall survival is poor and has not improved substantially over the last half century. It is clear that new approaches are needed and these should include prevention, screening for early detection, and novel treatments based on our understanding of the molecular biology of this disease. Recently attention has been drawn to the role of the cyclooxygenase (COX) enzyme and its involvement in tumorigenesis. Investigations have documented two isoforms, COX-1 and COX-2, encoded by different genes. COX-1 is constitutively expressed in most tissues and appears to be responsible for the production of prostaglandins mediating normal physiologic functions, such as the maintenance of gastric mucosa and regulation of renal blood flow. In contrast, COX-2 is normally undetectable in most tissues, and is induced by cytokines, growth factors, oncogenes, and tumor promoters. A growing body of evidence indicates COX-2 plays a key role in lung cancer, and can serve as a potential marker of prognosis in this disease. Furthermore, the recent availability of COX-2 inhibitor medications offers a unique opportunity to interfere with the development of lung cancer and the progression of metastasis. Because COX-2 inhibitors have been demonstrated to interfere with tumorigenesis, the COX-2 enzyme may be an attractive target for therapeutic and chemoprotective strategies in lung cancer patients.


   Introduction
Top
 Abstract
 Introduction
Lung cancer and COX-2
 Tumorigenesis of COX-2
 Conclusions
 Acknowledgments
 References
 
Lung cancer is the most common cause of cancer death in western countries, accounting for more deaths than prostate, breast, and colorectal cancer combined [1]. Current therapeutic approaches are ineffective for this disease, which is reflected by an overall survival of only 15% [2, 3]. Prognosis for lung cancer patients is strongly correlated with the stage of disease at diagnosis. Although surgical resection can provide lung cancer patients with the hope of cure, the long-term survival rate, even in the earliest stage of disease, is only 60% to 70% [3, 4]. Most patients who fail "curative" surgical therapy recur with distant disease, suggesting that even when the tumor is small and appears localized a high percentage of patients have occult metastases [5]. These patients would be ideal candidates for adjuvant therapy, especially since chemotherapeutic agents have a potentially greater effect on microscopic disease. Currently there is no means to predict this subset of patients, which may partially explain why chemotherapy for resected stage I lung cancer patients has not proven a significant benefit. Given the existing state of adjuvant therapies for lung cancer many physicians have adopted a conservative nihilistic approach.

Efforts to link genetic and biochemical markers with distinct clinical outcomes may be useful in defining subsets of lung cancer patients. As these subsets are identified, those more likely to develop recurrent disease may become candidates for adjuvant therapy. Each marker may not only define a unique tumor subset, but also provides a target for therapeutic intervention. Recent attention has been drawn to prostaglandins and cyclooxygenase (COX). The early findings of decreased colonic polyps in patients with familial adenomatous polyposis receiving nonsteroidal antiinflammatory drugs initiated interest in these molecules and their role in cancer [6]. Prostaglandin endoperoxide synthase 2 (COX-2), the inducible form of the COX enzyme, has been found to be overexpressed in a number of tumors with further implication in both tumorigenesis and metastases. A growing body of evidence supports that COX-2 plays a key role in lung cancer and can serve as a potential marker of poor prognosis in this disease. Furthermore, the recent availability of COX-2 inhibitors offers a unique potential to interfere with the development of lung cancer and the progression to metastasis. This review discusses what is known of COX-2 in tumorigenesis and possible mechanisms of action of the enzyme in lung cancer; and will further identify potential roles for COX-2 inhibition in the prevention and therapy of this disease.


   Lung cancer and COX-2
Top
 Abstract
 Introduction
 Lung cancer and COX-2
Tumorigenesis of COX-2
 Conclusions
 Acknowledgments
 References
 
Elucidating cellular pathways in cancer is not only vital to future therapy, but may provide new opportunities for early diagnosis. Cellular markers, such as mutant K-ras and TP53 genes, combined with advances in bronchoscopy (eg, laser-induced fluorescence endoscopic bronchoscopy), may make possible the detection of preinvasive and invasive lung cancer lesions in persons at high risk [7]. The detection of early lesions in at risk individuals would identify candidates for studies of chemoprevention. Chemoprevention is an additional option in persons at high risk for developing either recurrent cancer after resection or a second primary cancer [8].

An expanding body of evidence indicates that downregulation of COX enzymes will be an important strategy for preventing cancer, because COXs catalyze the formation of prostaglandins; compounds with multiple carcinogenic effects [9]. A number of prostaglandin synthesis inhibitors are effective in counteracting tumor development. Aspirin and aspirin-like nonsteroidal antiinflammatory drugs (NSAIDs) can inhibit colorectal tumorigenesis and are among the few agents reported to be useful for chemoprevention of neoplasia [10]. Recent investigations have documented two isoforms of COX, COX-1 and COX-2, encoded by different genes [11, 12]. Although both enzymes metabolize the conversion of arachidonate to prostaglandins and other eicosanoids, their expression and regulation are quite different. COX-1 is a constitutively expressed isoenzyme, crucial to normal cellular function, playing a particularly important role in healthy gastrointestinal and renal function. By contrast, COX-2 is an early response gene, which is inducible by cytokines, growth factors, and tumor promoters, and is largely responsible for the production of prostaglandins during inflammation [13].

COX-2 has been implicated as an important factor in tumorigenesis [14, 15]. The system best understood is colorectal cancer. More than 80% of human colorectal cancers have increased levels of COX-2 mRNA, as do 40% of colorectal adenomas [16]. COX-2 inhibitors (such as NSAIDs) exhibit dramatic antineoplastic activity in a number of experimental models of colorectal cancer. These include colon cancer cells implanted into nude mice, colon tumor production in adenomatous polyposis coli (APC) mutant mice, and carcinogen-induced colon tumors in rats [17–19]. Transfection of COX-2 into human colon cancer cells has revealed COX-2 to be involved in a number of processes fundamental to tumor development, including apoptosis, tumor invasion, angiogenesis, and metastasis [20–22]. COX-2 appears to modulate the expression of a large number of genes associated with these processes.

In addition to colon cancer, COX-2 is upregulated in multiple types of solid tumors, including carcinomas of lung, breast, prostate, and urinary bladder of humans and animals [23–25]. Inhibitors of COX-2 reduce the formation of intestinal, breast, skin, lung, bladder, and tongue tumors in experimental animal models [26]. NSAIDs nonspecifically inhibit the activity of COX-1 and COX-2; accounting for both therapeutic and adverse effects. Inhibition of COX-2 by NSAIDs explains the therapeutic use of antiinflammatory medications, and inhibition of COX-1 explains the unwanted side effects, such as gastric damage from using these drugs [27].

At least three lines of evidence strongly support a role for COX-2 in lung cancer development: (1) COX-2 is overexpressed in many lung cancers; (2) several selective and nonselective (eg, NSAIDs) COX-2 inhibitors prevent lung cancer in experimental animals in a dose-dependent manner; and (3) a limited number of epidemiologic studies support the suggestion that regular use of NSAIDs can reduce lung cancer incidence.

Several recent human nonpopulation-based studies of lung cancer have demonstrated expression of COX-2 in precursor lesions and in lung cancer tissue. COX-2 expression was found in atypical adenomatous hyperplasia, a possible precursor of adenocarcinoma of lung [28]. COX-2 expression was detected by immunohistochemical analysis in 19 of 21 lung adenocarcinomas [29]. In the same study, the enzyme was expressed in all 11 squamous cell carcinomas examined, although stain intensity was less [29]. In another study, COX-2 expression was found in 70% of 23 adenocarcinomas [30]. Further, its expression is markedly increased in most patients with bronchiolar-alveolar carcinoma [31]. Hida and colleagues [30] found increases in COX-2 immunoreactivity were often observed in tumor-invasive lesions and in lymph node metastases. Therefore, it was suggested that an increase in COX-2 expression may be associated with tumor progression of adenocarcinoma of the lung, and that COX-2 might play a role in the acquisition of an invasive and metastatic phenotype. A recent study found the level of COX-2 expression in nonsmall cell lung cancer (both adenocarcinoma and squamous cell carcinoma) to be significantly higher than in normal lung tissues [32]. Second, COX-2 levels were significantly higher in adenocarcinomas than squamous cell carcinomas [32]. Achiwa and coworkers [33] found strong COX-2 immunoreactivity in 93 of 130 adenocarcinoma patients (72%), and a significant relationship between elevated COX-2 expression and shortened patient survival was observed in a cohort of patients with stage I disease (p = 0.034). This suggests finding an increase in COX-2 expression may be clinically significant for the prognosis of patients undergoing surgical resection of early-stage adenocarcinomas. Further supporting this, Khuri and colleagues [34] reported that COX-2 overexpression portended a shorter survival among patients with resected early stage nonsmall cell lung cancers.

There is experimental evidence that selective and nonselective COX-2 inhibitors can protect against lung cancer development. Aspirin, sulindac, and NS398 (a selective COX-2 inhibitor) reduced lung cancer incidence in a dose-response manner in mice exposed to tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) [35, 36]. Indomethacin inhibited the accumulation of tumor cells in mouse lungs and subsequent growth of lung metastases after intravenous injection [37]. It has been demonstrated that the chemopreventive effects of acetylsalicylic acid and NS398 in the NNK-induced mouse lung tumor model were due to inhibition of COX-2 expression and induction of apoptosis [38]. Celecoxib, a selective COX-2 inhibitor, dose-dependently inhibited primary tumor growth, and the number and size of lung metastases in Lewis lung carcinoma cells and human colon carcinoma HT29 cells [39]. Meloxicam, a preferential COX-2 inhibitor, inhibited prostaglandin-E2 production and the growth of nonsmall cell lung cancer cell lines [40]. Finally, nimesulide, a selective COX-2 inhibitor, inhibits in vitro proliferation of nonsmall cell lung cancer cell lines in a dose-dependent manner at clinically achievable concentrations [41].

In addition, recent evidence finds COX-2 inhibition may be a useful adjunct to standard chemotherapy protocols, through a process of chemosensitization or synergism with existing chemotherapeutics [42]. Csiki and coworkers [43] recently reported the addition of celecoxib (400 mg, bid) with docetaxel in patients with lung cancer was associated with decreased levels of tumor prostaglandin-E2, with some patients exhibiting objective response to therapy. Subbaramaiah and colleagues [44] recently demonstrated that paclitaxel induces prostaglandin-E2 production, providing some insight as to the mechanism of improved tumor response when COX-2 inhibition is added to the treatment regimen. Care should be exercised when adding a COX-2 inhibitor to a chemotherapeutic regimen because the effects may not always be complimentary.

Concerning colon cancer, epidemiologic data are becoming available establishing a link between NSAIDs and lung cancer. Data from the National Health and Nutrition Examination Survey I (NHANES I) and the NHANES I Epidemiologic Follow-up Studies (NHEFS) revealed that the incidence of lung cancer was lower among persons who reported aspirin use: the incidence rate ratio (and 95% confidence interval) for lung cancer was 0.68 (0.49 to 0.94) [45]. Also, the association between aspirin use and lung cancer risk in women was examined in a case-control study nested in the New York University Women’s Health Study, a large cohort in New York. A stronger inverse association was observed in analyses restricted to nonsmall cell lung cancer (adjusted odds ratio 0.39, 95% confidence interval 0.16 to 0.96) [46]. These results suggest that regular aspirin use might be inversely associated with risk of lung cancer in women, particularly nonsmall cell lung cancer.

These data provide evidence that COX-2 plays a role in both tumorigenesis and the development of metastases. The early evidence that overexpression of this enzyme may be a marker of poorer prognosis is important because this may provide a means to define a subset of patients more likely to recur after resection, thereby defining possible candidates for adjuvant anticancer therapy. The evidence for COX-2 involvement in lung cancer poses the question as to what the effect of COX-2 inhibition on tumor growth and progression to metastases might be. To better understand the potential clinical applications of inhibiting this enzyme, a more detailed understanding of proposed tumorigenic mechanisms of COX-2 is needed.


   Tumorigenesis of COX-2
Top
 Abstract
 Introduction
 Lung cancer and COX-2
 Tumorigenesis of COX-2
Conclusions
 Acknowledgments
 References
 
To date, COX-2 has been implicated in several mechanisms where it contributes to tumorigenesis and the malignant phenotypes of tumor cells, included among them: inhibition of apoptosis, increased angiogenesis, and increased invasiveness.

Apoptosis
Induction of apoptosis is one of the most widely investigated and consistently supported potential mechanisms for the antineoplastic effect of COX-2 inhibitors (Fig 1). Apoptosis, or programed cell death, plays a major role in maintaining the integrity of cellular epithelium. For example, transformation of colorectal epithelia to adenomas and adenocarcinomas has been associated with a progressive loss of apoptosis [47]. Several recent studies provide evidence that one of the mechanisms by which COX-2 promotes tumorigenesis is by its inhibition on apoptosis. In vitro experiments indicated that modulation of COX-2 activity led to altered apoptotic propensity [20, 48]. Nimesulide, a COX-2 inhibitor, can inhibit proliferation in nonsmall cell lung cancer cell lines in vitro, in part by inducing apoptosis [41]. In the Min mouse model, COX-2 expression decreased apoptosis, a phenomenon reversed by sulindac [49]. Bcl-2, a proto-oncogene, is one of the main apoptosis regulatory proteins. In the colon cancer model, bcl-2 expression inhibited apoptosis in vivo [50], and preliminary in vitro data suggests that bcl-2 expression is induced by COX-2 [20]. Some findings also suggest that COX-2 promotes cell survival by upregulating the level of Mcl-1, a member of the bcl-2 family [51].



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  		Fig 1. A central role for cyclooxygenase-2 (COX-2) in apoptosis. COX-2 can be induced by a wide range of stimuli: EGF, LPS, and NNK. Inhibition of COX-2 results in decreased Bcl-2 and increased apoptosis. Similarly, inhibition of COX-2 results in accumulation of unesterified arachidonate, which is itself pro-apoptotic. COX-2 inhibitors have been found to induce apoptosis independent of the COX-2 enzyme. Their effects include the inhibition of NF-kappa-ß through IKK-ß, direct inhibition of Bcl-2, increased conversion of sphingomyelin to ceramide, inhibition of PPAR, and induction of 15-lipoxygenase. (Bcl-2 = B-cell leukemia proto-oncogene 2; EGF = epidermal growth factor; IKK-ß = IkappaB kinase-beta subunit; LPS = lipopolysaccharide; NF-Kappa-ß = transcription factor nuclear factor-kappa-ß; NNK = nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; PGs = prostaglandins; PPAR = peroxisome proliferator activator receptor.)

 
Many anticancer agents, including radiation, induce apoptosis as a mechanism of killing tumor cells [52–54], and COX-2 expressing cells may have some degree of resistance to apoptosis induced by these agents. In vitro and in vivo results suggest that selective COX-2 inhibitors enhance the effect of radiation on tumors expressing COX-2, but not on COX-2 lacking tumors [55]. This effect may be attributable to enhancing radiation-induced apoptosis.

Although the precise mechanistic basis remains uncertain, the suppression of apoptosis associated with COX-2 overexpression may be an important factor in tumorigenesis. Many NSAIDs, including selective COX-2 inhibitors, have been found to induce apoptosis in a variety of cells [41, 56–60]. These observations are consistent with the ability of COX-2 overexpression to suppress apoptosis. However, NSAID-induced apoptosis has been demonstrated in cell lines not expressing COX-2 [61–63], and non-COX inhibiting sulindac metabolites (such as sulindac sulfone) retain the ability to induce apoptosis [64, 65]. Thus, NSAIDs most likely stimulate apoptosis through COX-dependent and COX-independent mechanisms. Mechanisms involving different signaling targets have been proposed to account for NSAID-induced apoptosis in cancer cells. The putative mechanisms include inhibition of IKK-ß, thereby preventing nuclear factor-{kappa}-ß (NF-{kappa}-ß) activation [66, 67], inhibition of bcl-2 expression [68], accumulation of unesterified arachidonic acid [36], induction of 15-lipoxigenase-1 [69], conversion of sphingomyelin to ceramide, a known mediator of apoptosis [70], and inhibition of peroxisome proliferator-activated receptor (PPAR) [71]. For example, Berman and colleagues [67] found sulindac enhances tumor necrosis factor-{alpha} mediated apoptosis of lung cancer cell lines by inhibition of NF-{kappa}-ß. Cao and associates [72] demonstrated exogenous arachidonic acid causes apoptosis in colon cancer and other cancer cell lines. The inhibition of COX-2 by NS398 may result in the accumulation of arachidonic acid in cancer cells, thereby triggering apoptosis [60, 73]. Furthermore, expression of 15-lipoxygenase-1 (15-LOX-1), usually reduced in colorectal cancer, was induced by NS398 in colon cancer cells; this may have led to an increase in its product, 13-S-hydroxyoctadecadienoic acid (13-S-HODE), which can induce colon cancer cells to undergo apoptosis [69]. The APC protein can normally inhibit PPAR-{gamma} in colorectal cells and mutation of the APC gene is a major cause of colorectal carcinogenesis. NSAIDs can inhibit PPAR-{gamma} and may further inhibit colorectal carcinogenesis [71]. It is plausible that different COX-2 inhibitors mediate apoptosis through distinct mechanisms. However, whether COX-2 inhibition plays an obligatory role in the apoptotic effects of COX-2 inhibitors is yet to be resolved. At least one study was able to dissociate the apoptosis inducing activity of celecoxib from its COX-2 inhibitory action by structural modification of this drug [74]. It was determined that the effect of the COX-2 inhibitor celecoxib on apoptosis was independent of inhibition of COX-2 activity [74]. Treatment with celecoxib led to cell death, but COX-2 depletion did not. Several celecoxib derivatives lacking COX-2 inhibitory action have been characterized to be as potent in eliciting apoptosis in PC-3 cells as the parent compound [74]. Furthermore, the mechanism these derivatives and the parent compound, celecoxib, induced apoptosis remained the same, facilitating the dephosphorylation of Akt and ERK2 proteins [74]. The specific mechanisms of these COX-independent effects and their therapeutic implications are not well understood. However, some of the studies demonstrating effects on COX-independent pathways utilize concentrations of NSAIDs (100 to 1000 µmol/L) that are difficult to achieve in living organisms without severe toxic side effects.

Angiogenesis
In colon carcinoma a recent study demonstrated that transfection of COX-2 into colorectal cancer cells produces prostaglandins and proangiogenic factors that stimulated the initial steps of angiogenesis [21] (Fig 2). Aspirin, NS398 (a selective COX-2 inhibitor), and antibodies against vascular endothelial growth factor (VEGF) abrogated this process. Furthermore, COX-2 transfected cells induced expression of VEGF [21]. Another study demonstrated COX-2 derived prostaglandins mediated tumor growth and metastasis in two independent animal models of lung and colon tumors, and in fibroblast growth factor-2 (FGF-2) induced corneal neoangiogenesis. Subsequently, celecoxib demonstrated potent antiangiogenic activity in vivo, with a consequent antitumor effect [39]. Among products of the COX-2 pathway, prostaglandin-E1 and prostaglandin-E2 are reported to promote angiogenesis [75]. In contrast, 15-deoxy-prostaglandin-J2, a product from prostaglandin-D2, inhibits angiogenesis [75]. Therefore, the actual profile of downstream COX metabolites rather than the level of COX protein or activity is more relevant in angiogenesis regulation. Among them, thromboxane-A2 has been demonstrated as the mediator of COX-2 dependent angiogenesis and regulates endothelial cell migration [76, 77].



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  		Fig 2. Cyclooxygenase-2 (COX-2) induction stimulates mediators of angiogenesis. PGE2, PGE1, and COX-2 stimulate VEGF, a potent stimulator of endothelial neovascularization. PGE2 also affects FGF, resulting in increased angiogenesis. TXA-A2 has also been implicated in cellular migration. (FGF = fibroblast growth factor; PGE1 = prostaglandin-E1; PGE2 = prostaglandin-E2; PGD2 = prostaglandin-D2; TXA-A2 = thromboxane A2; VEGF = vascular endothelial growth factor.)

 
Despite our better understanding of the role of COX in angiogenesis, many questions remain unanswered. For example, how does COX upregulate the angiogenic potential of tumor cells? Are COX products angiogenic? Do VEGF and other angiogenic factors require COX activity to elicit an angiogenic response? Further research should be focused on the mechanistic involvement of COX-2 in endothelial cell angiogenic responses [75].

Invasion-metastasis
E-cadherin, an epithelial adhesion molecule, is critical for the maintenance of cell polarity and differentiation (Fig 3). Downregulation of E-cadherin has been reported to occur in a variety of solid tumors and is closely correlated with tumor invasion [76, 77]. E-cadherin negative tumor cells are far more likely than E-cadherin positive cells to detach from a tumor mass, pointing to a mechanism whereby defects in cell–cell adhesion could lead to tumor cell dissemination [78]. COX-2 has been found to decrease expression of E-cadherin [78], and transfection of COX-2 in human colon cancer cells confers increased capability for invasiveness [20]. To date, few studies have demonstrated the importance of COX-2 in modulating the invasive properties of human cancer cells. Human colon cancer carcinoma cells transfected with a COX-2 expression vector exert increased prostaglandin production and acquired greater invasiveness compared with control cells [21].



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  		Fig 3. Cyclooxygenase-2 (COX-2) role in invasion and metastasis. Increases in prostaglandins (PGE2) are implicated in downregulation of E-cadherin with decreased cellular adhesion. An increase in MMP has been associated with COX-2 activation, which can be attenuated by COX-2 inhibition. PGE2 upregulates VEGF and has both autocrine and paracrine effects in an "autofeedback" system to further upregulate COX-2. COX-2 production by tumor cells has been found to increase levels of IL-10 and decrease levels of IL-12, resulting in a decrease of tumor induced immune response. (CD-44 = cluster of differentiation-44; FGF = fibroblast growth factor; IL = interleukin; L= lymphocyte; MMP = matrix metalloproteinase; PGE2 = prostaglandin-E2; VEGF = vascular endothelial growth factor.)

 
Increased invasiveness has also been associated with activation of matrix metalloproteinase-2 (MMP-2) and increased mRNA expression of MMP-1 [79]. Matrix metalloproteinases are a family of degradative enzymes linked to several malignant properties of tumor cells. Their expression is associated with tumor cell invasion of the basement membrane, stroma, blood vessel, and subsequent metastasis [80]. Both effects are reversed by treatment with sulindac sulfide [21]. Similar results were reported using a human prostate tumor cell line DU-145, where COX-2 inhibition resulted in altered secretion of MMP-2 and MMP-9, suggesting COX-2 may control MMP activity [81]. Several lines of evidence support the proposed involvement of COX-2 in the production and secretion of MMPs [82, 83]; however, underlying biologic mechanisms are not fully understood. Finally, Pan and coworkers [84] investigated the effect of a COX-2 selective inhibitor, NS398, on the expression and enzymatic activity of MMPs in human lung cancer cells. Their results indicate NSAIDs suppress MMP-2 expression by repression of gene transcription. Because the concentration of NS398 needed to suppress expression of MMP-2 is much higher than the concentration of NS398 needed to block enzymatic COX-2 activity, they speculate that the effect of NS398 on MMP-2 is not fully dependent on inhibition of COX-2 activity [84].

Indirectly related to the metastatic potential of tumors is the COX-2 mediated inhibition of antitumor immunity, in part regulated by interleukin-10 (IL-10) and IL-12 [85, 86]. IL-10 produced by tumor cells and cells in the stromal environment (including lymphocytes and macrophages), is a potent suppressor of antitumor immunity, whereas IL-12 is a cytokine related to cell-mediated antitumor immunity [87, 88]. COX-2 production by tumor cells has been demonstrated to increase levels of IL-10 and decrease levels of IL-12, resulting in a decrease of tumor-induced immune response [86]. COX-2 inhibition has been reported to reduce prostaglandin-E2 and IL-10 production by tumor tissues [86, 88]. Furthermore, it appears that COX-2 dependent tumor invasion is mediated by the extracellular matrix receptor CD44 [89].


   Conclusions
Top
 Abstract
 Introduction
 Lung cancer and COX-2
 Tumorigenesis of COX-2
 Conclusions
Acknowledgments
 References
 
Numerous epidemiologic, experimental, and clinical studies indicate NSAIDs, particularly selective COX-2 inhibitors, reveal promise as anticancer drugs. However, the clinical application of these drugs is still limited by a lack of evidence indicating efficacy in populations other than those with familial adenomatous polyposis, and endpoints other than adenomatous colorectal polyps. In addition, questions regarding the mechanisms of drug action, the optimal drug doses, and treatment regimens exist. Further investigation is warranted to determine the putative role of COX-2 in development and progression of lung cancer. Studies are needed to establish whether the enzyme encoded by this gene represents a suitable target for chemopreventive strategies. Such insight would be especially significant for future clinical applications, potentially leading to a reduction in the high death rate from this disease. It is crucial to determine whether COX-2 expression of a particular carcinoma is an independent prognostic factor and whether inhibition of this enzyme impacts on growth or metastases of the tumor. Sufficient data exists, suggesting COX-2 inhibition may indeed prove to be a preventative tool in high-risk patients, and may play an adjunct role with chemotherapy in patients with different stages of disease. Given that lung cancer is one of the most common cancers in the United States, and COX and COX-2 selective inhibitors are now commercially available, defining the actions of COX-2 and the effects of COX-2 inhibition carries major significance in the prevention and therapeutics of lung cancer.


   Acknowledgments
Top
 Abstract
 Introduction
 Lung cancer and COX-2
 Tumorigenesis of COX-2
 Conclusions
 Acknowledgments
References
 
The authors thank Roberto Salazar and Roberto Castaños for their time and effort. This study was supported by a grant from the Hastings Foundation, Pasadena, California.


   References
Top
 Abstract
 Introduction
 Lung cancer and COX-2
 Tumorigenesis of COX-2
 Conclusions
 Acknowledgments
 References
 

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