Inflammation in lung carcinogenesis: New targets for lung cancer chemoprevention and treatment
Introduction
Lung cancer is the leading cause of cancer-related mortality in the United States and is responsible for more deaths than prostate, colon, and breast cancers combined [1]. The overall 5-year survival rate is less than 15% for patients with lung cancer, which has remained largely unchanged for the last three decades. Understanding the molecular mechanisms involved in the pathogenesis of lung cancer can provide opportunities to develop innovative therapies for non-small cell lung cancer (NSCLC). The acquisition of genetic mutations facilitates cancer development and malignant phenotype. These mutations are critically linked to acquiring cellular properties associated with apoptosis resistance, unregulated proliferation, invasion, metastasis, and angiogenesis. Inflammation has been postulated to play a key role in lung carcinogenesis. There is a growing body of evidence to suggest that smoking induced pulmonary inflammation increases lung cancer development in smokers [2], [3]. In addition, the regular use of aspirin and other non-steroidal anti-inflammatory drugs is associated with reduced risk of developing lung cancer in animal models and in smokers [3], [4]. Cyclooxygenase 2 (COX-2) has been implicated in apoptosis resistance, angiogenesis, decreased host immunity, and enhanced invasion and metastasis, and thus has a critical involvement in carcinogenesis. COX-2 is one of the novel targets being studied for lung cancer therapy and chemoprevention [5], [6].
Section snippets
COX-2
Cyclooxygenase (also referred to as prostaglandin endoperoxidase or prostaglandin G hydroperoxide synthase) is the rate-limiting enzyme for the production of eicosanoids prostaglandins (PGs) and thromboxanes (TXs) from free arachidonic acid, which is released from the membrane phospholipids by phospholipase A2 [7]. Cyclooxygenase is bound to the cytosolic side of the endoplasmic reticulum and cell membrane [8]. It is a bifunctional enzyme, with fatty acid cyclooxygenase (COX) activity producing
COX-2 and lung cancer
Several studies have demonstrated high-level constitutive COX-2 expression in human NSCLC [20], [21], [22], [23], [24], [25], [26], [27], [28], [29]. In the initial report describing COX-2 in human lung cancer, Huang et al. assessed COX-2 expression in NSCLC and normal adjacent lung tissue of resected specimens by immunohistochemistry [20]. All of the 15 tumor specimens (8 adenocarcinomas and 7 squamous cell carcinomas) showed cytoplasmic staining for COX-2 in tumor cells. In contrast, adjacent
COX-2 downstream signaling: prostanoid receptors
The prostanoid receptors are in the superfamily of G protein-coupled receptors. PGE2 exerts its multiple effects through four GPCRs designated as EP1, EP2, EP3 and EP4 [11]. Studies of the receptor subtypes have shown that the EP1 receptor acts via Gq protein and upon activation increases cellular Ca2+ level. Studies indicate EP1 receptors can be localized not only on the cell membrane but also on the nuclear membrane [42]. The EP2 and EP4 receptor signaling is mediated by Gs G-proteins and
Complicity of host cellular networks in lung tumorigenesis
The pulmonary environment presents a unique milieu in which lung carcinogenesis proceeds in complicity with the host cellular network. The pulmonary diseases that are associated with the greatest risk for lung cancer are characterized by abundant and deregulated inflammation [47], [48], [49]. Pulmonary disorders such as chronic obstructive pulmonary disease (COPD)/emphysema and pulmonary fibrosis are characterized by profound abnormalities in inflammatory–fibrotic pathways [50], [51], [52]. For
Reversal of epithelial mesenchymal transition
EMT requires alterations in the cell morphology, adhesion, and migration [58]. These cellular changes result in variable expression of proteins which define EMT markers. Decreased e-cadherin level is a hallmark feature of EMT, which allows reduction in cell to cell adhesion and enhances migratory capacity [58]. We have previously shown a COX-2-dependent transcriptional regulation of e-cadherin expression and cellular aggregation in NSCLC, and a reciprocal relationship between COX-2 and
Immunosuppression
It was originally hypothesized more than 30 years ago that specialized T cell subpopulations existed that functioned to suppress immune responses [70]. North and others pursued this avenue of investigation within the context of tumor immunity [71], [72]. However, these early studies in the field of suppressor T cells were stymied by an inability to characterize the cellular and molecular mechanisms responsible for the observed suppressive phenomena. There has been a renewed interest in the
Interaction between COX-2 and EGFR signaling
Studies demonstrating that EGFR and COX-2 have related signaling pathways that can interact to regulate cellular proliferation, migration and invasion [98], [99], [100], [101], [102] have triggered interest in evaluating the combination of COX-2 and EGFR inhibition in NSCLC. Coffey et al. [100] demonstrated that the activation of EGFR by transforming growth factor alpha stimulates COX-2 production resulting in increased release of PGE2 and increased mitogenesis. They also showed that COX-2
COX-2 clinical trials
Based on these findings, recent studies have been conducted evaluating combined inhibition of the EGFR and COX-2 pathways in patients with NSCLC. Gadgeel et al. [110] reported a Phase II study of gefitinib and celecoxib in patients with platinum refractory NSCLC. Patients received gefitinib 250 mg daily and celecoxib 400 mg twice daily. The response rate to the combination of celecoxib and gefitinib was similar to that observed with gefitinib alone. O’Byrne [111] recently reported a Phase I/II
Conclusion
Lung carcinogenesis is a complex process involving the acquisition of genetic mutations that lead to cancer development and the malignant phenotype. These mutations are critically linked to cellular changes, such as apoptosis resistance, unregulated proliferation, invasion, metastasis, and angiogenesis. Elucidation of the molecular mechanisms involved in these cellular changes provides opportunities to develop innovative therapies. COX-2 has been implicated in apoptosis resistance,
Reviewer
Prof. Giorgio V. Scagliotti, University of Turin, Department of Clinical and Biological Sciences, S. Luigi Hospital, Thoracic Oncology Unit, Regione Gonzole 10, I-10043 Turin, Italy.
Steven M. Dubinett, M.D., is a Professor of Medicine and Pathology, Director, UCLA Lung Cancer Research Program in the Jonsson Comprehensive Cancer Center, Chief, Division of Pulmonary and Critical Care Medicine, and Principal Investigator for the UCLA Lung Cancer SPORE. His laboratory has identified important inflammation-dependent genes and proteins mediating angiogenesis, apoptosis resistance, invasion and immune suppression in non-small cell lung cancer. He has made translational
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Steven M. Dubinett, M.D., is a Professor of Medicine and Pathology, Director, UCLA Lung Cancer Research Program in the Jonsson Comprehensive Cancer Center, Chief, Division of Pulmonary and Critical Care Medicine, and Principal Investigator for the UCLA Lung Cancer SPORE. His laboratory has identified important inflammation-dependent genes and proteins mediating angiogenesis, apoptosis resistance, invasion and immune suppression in non-small cell lung cancer. He has made translational contributions related to the microenvironment, inflammation and epithelial mesenchymal transition in the pathogenesis of lung cancer.
Jay M. Lee, M.D., is an Assistant Professor of Surgery, Division of Cardiothoracic Surgery, and Surgical Director, UCLA Thoracic Oncology Program. He is devoted to translational research in understanding inflammation and immunobiology of lung carcinogenesis within the Lung Cancer Research Program in the Jonsson Comprehensive Cancer Center.
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