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(Chest. 2004;125:134S-140S.)
© 2004 American College of Chest Physicians

Cyclooxygenase-2 in Lung Carcinogenesis and Chemoprevention*

Roger S. Mitchell Lecture

Joanne R. Brown, PhD and Raymond N. DuBois, MD, PhD

* From the Department of Gastroenterology and Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN.

Correspondence to: Raymond N. DuBois, MD, PhD, Vanderbilt-Ingram Cancer Center, 691 Preston Research Building, 2300 Pierce Ave, Nashville, TN 37232-6838; e-mail: raymond.dubois{at}vanderbilt.edu


   Introduction
TOP
 Introduction
COX Expression in Lung...
 COX-2 Activity and Its...
 The Future for Nonsteroidal...
 References
 
Lung cancer presents a major health problem in the world, with the highest rates seen in North America and northwestern Europe.1 During 2001, 169,500 new cases were presented in the United States, with 157,400 people dying of lung cancer.2 In fact, more people die from lung cancer than of colon, breast, and prostate cancers combined.3 Non-small cell lung cancers (NSCLCs) [adenocarcinoma, squamous cell carcinoma, large cell anaplastic carcinoma, and undifferentiated carcinomas] represent approximately 80% of all lung carcinomas. Of patients with NSCLC, surgery is the preferred option for resectable cases, providing success in only one fourth of patients due to frequent recurrence. Similarly, chemotherapy, which is used in advanced disease, provides limited survival and has considerable toxicity.4 Unfortunately, the most common NSCLC subtype, adenocarcinoma, has usually metastasized before clinical symptoms become apparent, thereby reducing treatment options and ensuring a poor outcome.5 Despite intensive research, the overall 5-year survival rate is only 8 to 14%, and has improved marginally during the past 25 years.6 Novel approaches for the management of lung cancer are urgently needed. Enormous efforts have been made to identify risk factors associated with the development of lung cancer and to explore potential preventive therapies. One such potential therapeutic target is the cyclooxygenase (COX) enzyme. Recent evidence suggests an important role of the inducible COX-2 isoform during the development of lung cancer.6 Precursor lesions express high levels of COX-2, COX-2 expression is associated with poor prognosis, and early data imply the use of selective COX-2 inhibitors may provide some benefit for prevention and/or treatment of lung cancer. This review will discuss the current role of COX-2 in lung cancer and how selective targeting may prove to add benefit for the treatment of lung cancer.


   COX Expression in Lung Cancer
TOP
 Introduction
 COX Expression in Lung...
COX-2 Activity and Its...
 The Future for Nonsteroidal...
 References
 
COX is the key enzyme in the conversion of arachidonic acid to prostanoids, potent bioactive lipid derivatives that participate in normal growth responses and in aberrant cellular growth, particularly during tumorigenesis. Since the identification of two isoenzymes of COX, the mitogen-inducible COX-2 isoform has received considerable attention for its potential role in epithelial tumorigenesis.7 COX-1, the constitutive isoform, is present in most tissues and is thought to function as a "housekeeping" gene, responsible for normal physiologic function. Conversely, COX-2 is dramatically up-regulated by a wide variety of stimuli, such as interleukin (IL)-1, tumor necrosis factor (TNF)-{alpha}, platelet-derived growth factor, epidermal growth factor, lipopolysaccharide, and phorbol esters. Clinically, COX-2 gene expression is elevated in gastric, hepatic, esophageal, pancreatic, head and neck, colorectal, breast, bladder, cervical, endometrial, skin, as well as lung cancers, when compared to matched normal tissue.8 In lung cancer, COX-2 expression is associated throughout tumor progression, since 100% of NSCLC preinvasive precursors as well as invasive lung cancers express COX-2.91011 COX-2 messenger RNA12 and protein91314 levels are high in well-differentiated lung adenocarcinomas, but low in poorly differentiated adenocarcinomas and squamous cell carcinomas, and undetectable in small cell lung cancers. Recently, increased COX-2 expression has also been associated with increased downstream eicosanoid synthase expression, such as prostaglandin E synthase, prostaglandin D synthase, and thromboxane A synthase.15 Finally, markedly higher COX-2 expression has been observed in lung cancer metastatic to lymph nodes.9 The prognostic significance of this increased COX-2 expression has been reported. A number of studies have shown a correlation between COX-2 expression and poor prognosis, in which COX-2 protein elevation in stage I disease adenocarcinoma samples conferred poor prognosis,16 and increased COX-2 messenger RNA levels portend a worse overall survival rate17 and aggressive disease18 in NSCLC. These reports suggest a role for COX-2 in the pathogenesis of lung cancer. The precise mechanism whereby COX-2 expression is increased in lung cancer is not completely understood. However, COX-2 may directly impact on lung cancer since the COX-2 enzyme can activate environmental carcinogens such as the tobacco smoke carcinogen benzo[a]pyrene.19 Conversely, benzo[a]pyrene itself can up-regulate COX-2 expression and prostaglandin E2 (PGE2) production.20 Many other stimuli present in the pulmonary microenvironment that are associated with an increased risk of lung cancer can also increase COX-2 expression.6 The genetic basis of COX-2 expression in lung cancer with respect to inflammatory-related genes has identified allelic polymorphisms in the 3' untranslated region of the COX2/PTGS2 gene.21 This may provide a mechanism where controlling messenger RNA stability and degradation contributes to the constitutive expression of COX-2 and increased risk of developing lung cancer.


   COX-2 Activity and Its Multifaceted Role in Lung Cancer
TOP
 Introduction
 COX Expression in Lung...
 COX-2 Activity and Its...
The Future for Nonsteroidal...
 References
 
The role of COX-2 in malignant and metastatic disease has been shown to involve inhibition of apoptosis, stimulation of angiogenesis, subversion of the immune system, and promotion of tumor invasion. These areas of research will be discussed below.

Apoptosis
Early tumor growth is dependent on the balance between increased proliferation and decreased cell death. As this imbalance continues, the overall effect results in increased tumor size. Within the hostile and often hypoxic tumor environment, genetic changes allow cells to acquire mutations resulting in resistance to apoptosis and increased metastatic potential. A number of hallmark studies have demonstrated the role of COX-2 in this process (reviewed in Gupta and DuBois7). Forced COX-2 expression in normal intestinal epithelial cells results in a resistance to undergo apoptosis with increased bcl-2 expression, increased avidity to extracellular matrix components, reduced transforming growth factor-ß receptor expression,22 and a prolongation of the G1 phase of the cell cycle.23 This increased survival has also been seen in lung adenocarcinoma cells forced to express COX-2.24 Inhibition of COX-2 results in induction of apoptosis in lung carcinoma cells.252627 The mechanism whereby elevated COX-2 may confer protection against apoptosis in lung cancer cells has recently been investigated: similar to intestinal epithelial cell malignancy, forced COX-2 expression in lung cancer cells increased Mcl-1 levels, a bcl-2 family member.24 However, a bcl-2–independent pathway has also been identified and would appear to be associated with the antiapoptotic protein survivin.28 However, COX-independent antiapoptotic mechanisms may also be operative in these systems, perhaps when using high drug concentrations (reviewed by Soh and Weinstein29). Many anticancer agents such as chemotherapy kill tumor cells through the induction of apoptosis. Since these agents also have the ability to induce the expression of COX-2 in many cell types,30313233 this additional level of protection afforded by the tumor cells needs to be addressed. Therefore, the ability of selective COX-2 inhibitors to induce apoptosis is of particular importance when considering their potential application for combination use with chemotherapy and/or radiation therapy.

Angiogenesis and Invasiveness
Within the tumor microenvironment, the maintenance of a functional and constant vascular supply is required for malignancies to progress beyond a few millimeters3 in size, and for subsequent propagation, invasion, and metastasis. Therefore, angiogenesis—the formation of new blood vessels from a preexisting vasculature—is a prerequisite for successful tumor growth.34 Growth factors such as vascular endothelial cell growth factor (VEGF),35 basic fibroblast growth factor,36 and transforming growth factor-ß,37 as well as cytokines such as IL-838 have already been implicated in the sustained vascular supply in lung cancer. Genetic mutations of various oncogenes and tumor suppressor genes and dysregulated immune responses are associated in the complex regulation of these angiogenic mediators.39 The angiogenic component in tumors is therefore a potentially important therapeutic target.

Prostaglandins have been known to contribute to tumor development through their role in angiogenesis.40 Studies now show clear evidence for the role of COX-2 activity in the development of tumor-induced angiogenesis. For example, COX-2 expressing colorectal cancer cells can induce an angiogenic response in endothelial cells, while endothelial cell-derived COX-1 may also play a significant role in the angiogenic response.41 However, in vivo models of lung cancer-induced angiogenesis demonstrate that COX-2 appears to be the dominant isoform. In a model of syngeneic lung tumor growth, COX-2 expression correlated with tumor-associated neoangiogenesis, such that selective COX-2 inhibition significantly reduced tumor growth.42 In keeping with this, host-derived COX-2 products were shown to be instrumental for sustained tumor growth, since lung cancer cells injected into syngeneic mice bearing a genetic background of COX-2 (but not COX-1) deficiency were less able to support tumor growth.43 Fibroblasts were the main source of increased VEGF expression, implying an intracrine effect by COX-2-derived prostaglandins from stromal cells resulting in increased VEGF and a proangiogenic effect on neighboring endothelial cells.44 These studies are consistent with angiogenic markers and COX-2 in human lung sections, such that COX-2 expression correlates with VEGF expression.45

COX-2 can also regulate lung cancer invasion, vital for the dissemination of metastatic cells across extracellular matrix and spread to distant organ sites. Lung cancer cells overexpressing COX-2 (producing increased PGE2) also display concomitant increased CD44 expression, a cell receptor for the matrix glycosaminoglycan hyaluronon.46 In fact, antibody-mediated blockade of COX-2-derived PGE2 was sufficient to decrease both CD44 and matrix metalloproteinase-2 expression as well as invasion in a EP4-dependent manner.47 Exposure of NSCLC cells to dimethyl-PGE2 up-regulated CD44, EP4, and matrix metalloproteinase-2 expression and potently enhanced invasion.

Immune Modulation
Chronic immune activation along with the genetic predisposition of the individual is crucial for carcinogen-induced malignancy to progress in the pulmonary microenvironment. For example, although the majority of cigarette smokers never acquire lung cancer; many individuals do so through passive smoking.48 Immune activation can be broadly divided into cell-mediated immunity, producing predominantly T-helper type 1 (Th1) cytokines: interferon-{gamma}, IL-2, and TNF-{alpha}; and humoral immunity, producing predominantly T-helper type 2 (Th2) cytokines: IL-2, IL-6, and IL-10. Cell-mediated immunity is critically important for active and successful elimination of tumor growth since these cytokines are generally considered as proinflammatory and antiangiogenic.495051 Unfortunately, the lung cancer microenvironment hosts wide disparities in the profile of protumor and antitumor mediators, in favor of protumorigenic factors.6 Th2 cytokines such as IL-4 and IL-10, whose dominance will inhibit Th1 cytokines, are produced in COX-2–expressing environments such as lung cancer tissue.48 For example, Lewis lung carcinoma (LLC) cells grown in IL-10–null mice grow much faster than in wild-type mice.52 This demonstrates that overproduction of IL-10 prevents the development of an effective immune response against the tumor.

Recent data have shown COX-2 (but not COX-1)–producing lung cancer cells can have a profound immunosuppressive effect.13 PGE2 derived from COX-2 in A549 cells (lung adenocarcinoma cell line) can induce IL-10 in lymphocytes and macrophages; this Th2 imbalance was reversed by specific COX-2 inhibition.13 Similar results were observed when lung cancer was induced in COX-2–null mice; specific inhibition of COX-2 reduced LLC growth by increasing T-cell infiltration with induced Th1 cytokine production.53 This reversal of COX-2-specific Th1 cytokine production from Th2 cytokine predominance has recently been shown to abrogate colorectal metastatic tumor growth in vivo.54

The ability of PGE2 to potently influence the switch between a T-cell repertoire from Th1 to predominantly Th2 cytokines must involve antigen-presenting cells, since antitumor immune responses require the coordinate interaction of professional antigen presenting cells (dendritic cells [DCs] and macrophages) and effector lymphocytes. Advanced cancer is associated with impaired differentiation and antigen-presenting functions of DCs and their precursors. Soluble mediators isolated from cancer cells of excised tumors of the colon, breast, kidney, and skin can impair DC differentiation and maturation through increased Th2 cytokines (IL-6 and IL-10) and PGE2 levels.55 In lung cancer, studies indicate that COX-2 metabolites can play a major role in tumor-induced inhibition of DC differentiation, as inhibition of COX-2 expression or activity can prevent tumor-induced suppression of DC activities.56 This restricted DC function may be mediated through the EP2 receptor since the numbers of DCs, CD4+, and CD8+ T-cells were increased in EP2-null mice bearing LLC or colorectal tumors.57

The interplay between IL-10 and COX-2 expression is important depending on the cell type. IL-10 can down-regulate COX-2 protein expression in normal cells; however, in NSCLC cells, IL-10 cannot down-regulate COX-2 protein because these cells do not express functional IL-10 receptor.58 Therefore, this regulatory feedback loop allows unregulated COX-2 expression and PGE2 production as well as heightened IL-10 levels within the lung microenvironment (Fig 1 ).



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  		Figure 1. Schematic diagram representing the potential cellular interplay involved in the regulation of COX-2 expression within the lung tumor microenvironment. Chronic exposure to carcinogens can induce not only initiation of lung epithelial cells, but also induce inflammation (macrophage [MØ]) and immune activation (T-cell producing Th2-like cytokines), which can exacerbate the predisposition to malignancy through enhanced angiogenesis. PGE2 functions through its cognate EP receptors via autocrine and paracrine mechanisms to accelerate malignancy. One signaling pathway involved in PGE2 targeting has been shown to interact and transactivate the epidermal growth factor receptor (EGFR) leading to enhanced tumor cell migration and invasion.59 NFkB = nuclear factor-{kappa}B; MMP = matrix metalloproteinase; bFGF = basic fibroblast growth factor; IGF = insulin-like growth factor; EC = endothalial cell; PI-3K = phosphoinositol 3-kinase; Akt = atypical protein kinase B.

 

   The Future for Nonsteroidal Anti-inflammatory Drugs in the Treatment of Lung Cancer
TOP
 Introduction
 COX Expression in Lung...
 COX-2 Activity and Its...
 The Future for Nonsteroidal...
References
 
The clinical association between reduced epithelial cancer risk and nonsteroidal anti-inflammatory drugs (NSAIDs) has been recognized for > 20 years.60 Increased PGE2 levels have been noted in BAL fluid from patients with primary lung cancer with or without advanced metastatic disease.61 Regular aspirin and NSAID usage has been associated with an approximate 61 to 68% reduced risk and incidence in lung cancer, as shown in some epidemiologic studies.626364 However, these results are not conclusive, as another epidemiologic study failed to show a protective effect of regular NSAID use.65 Further studies are needed to elucidate treatment regimens, using long-term criteria designed to evaluate lung cancer outcome and incorporating new NSAID preparations, including selective COX-2 inhibitors. In vivo, NSAIDs have been shown to be effective in treating mice with carcinogen-induced lung cancer6667 and experimental metastasis.68 More recently, selective COX-2 inhibitors also display antitumor activity in other models of lung cancer,69 although the mechanism of this antitumor property may involve anti-inflammatory activities.5 However, genetic deletion of COX-2 can prevent the development of lung cancer growth.37 These preclinical results provide optimism for the use of selective COX-2 inhibitors within clinical settings.

Further preclinical data have provided evidence to suggest the use of selective COX-2 inhibitors combined with traditional anticancer therapeutics may provide additive or synergistic effects and thus be more beneficial than monotherapy. NS-398, a selective COX-2 inhibitor, can enhance the effect of radiation treatment in COX-2 (but not non–COX-2)-expressing colorectal cancer cells in vitro and in vivo increasing radiosensitivity.370 A similar effect has also been demonstrated in sarcoma cells in vivo using SC-236,7172 and celecoxib,73 two other selective COX-2 inhibitors operating through the additional inhibition of angiogenesis.71

Recently, the clinical potential of combined COX-2 inhibition (using celecoxib) with cytotoxic chemotherapy as a preoperative treatment for lung cancer was explored.74 The rational for this study was to investigate whether paclitaxel and other microtubule-interfering agents could induce COX-2 and prostaglandin production, and possibly reduce the efficacy achieved by paclitaxel. The authors found reduced PGE2 levels with combination treatment. Additional observations showed good tolerability and no impaired wound healing. Overall mortality and morbidity were 4% and 28%, respectively, of which 17% received a complete clinical response.7475 It was concluded that the addition of celecoxib may enhance the response to preoperative paclitaxel/carboplatin in NSCLC. Finally, trials are ongoing using celecoxib as a chemopreventive agent targeting large populations of high-risk individuals such as current and former smokers, and evaluating reliable molecular markers/end points to identify treatment efficiency (reviewed by Dubinett et al6).


   Footnotes
 
Abbreviations: COX = cyclooxygenase; DC = dendritic cell; IL = interleukin; LLC = Lewis lung carcinoma; NSAID = nonsteroidal anti-inflammatory drug; NSCLC = non-small cell lung cancer; PGE2 = prostaglandin E2; Th1 = T-helper type 1; Th2 = T-helper type 2; TNF = tumor necrosis factor; VEGF = vascular endothelial cell growth factor


   References
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 Introduction
 COX Expression in Lung...
 COX-2 Activity and Its...
 The Future for Nonsteroidal...
 References
 

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