Increased pulmonary production of prostaglandin I 2 (prostacyclin) by lung-specific overexpression of prostacyclin synthase decreases lung tumor incidence and multiplicity in chemically induced murine lung cancer models. We hypothesized that pulmonary prostacyclin synthase overexpression would prevent lung carcinogenesis in tobacco-smoke exposed mice. Murine exposure to tobacco smoke is an established model of inducing pulmonary adenocarcinomas and allows for the testing of potential chemopreventive strategies. Transgenic FVB/N mice with lungspecific prostacyclin synthase overexpression were exposed to mainstream cigarette smoke for 22 weeks and then held unexposed for an additional 20 weeks. All of the exposed animals developed bronchiolitis analogous to the respiratory bronchiolitis seen in human smokers. The transgenic mice, when compared with smoke-exposed transgene negative littermates, had significant decreases in tumor incidence and multiplicity. Significantly fewer transgenics (6 of 15; 40%) developed tumors compared with the tumor incidence in wild-type littermates (16 of 19; 84%; Fisher's exact test, P ؍ 0.012). Tumor multiplicity was also significantly decreased in the transgenic animals (tg ؉ ؍ 0.4 ؎ 0.5 versus wild-type ؍ 1.2 ؎ 0.86 tumors/mouse; P < 0.001). Targeted prostaglandin levels at the time of sacrifice revealed significantly elevated prostaglandin I 2 levels in the transgenic animals, coupled with significantly decreased prostaglandin E 2 levels. Gene expression analysis of isolated type II pneumocytes suggests potential explanations for the observed chemoprevention, with Western blot analysis confirming decreased expression of cytochrome p450 2e1. These studies extend our previous studies and demonstrate that manipulation of prostaglandin production distal to cyclooxygenase significantly reduces lung carcinogenesis in a tobacco smoke exposure model, and gene expression studies show critical alterations in antioxidation, immune response, and cytokine pathways.
Overexpression of prostacyclin synthase (PGIS) decreases lung tumor multiplicity in chemical-and cigarette-smoke-induced murine lung cancer models. Prostacyclin signals through a single G-protein-coupled receptor (IP), which signals through cyclic AMP. To determine the role of this receptor in lung cancer chemoprevention by prostacyclin, PGISoverexpressing mice were crossed to mice that lack the IP receptor [IP(−/−)]. Carcinogeninduced lung tumor incidence was similar in IP(+/+), IP(+/−), and IP(−/−) mice, and overexpression of PGIS gave equal protection in all three groups, indicating that the protective effects of prostacyclin are not mediated through activation of IP. Because prostacyclin can activate members of the peroxisomal proliferator-activated receptor (PPAR) family of nuclear receptors, we examined the role of PPARγ in the protection of prostacyclin against lung tumorigenesis. Iloprost, a stable prostacyclin analogue, activated PPARγ in nontransformed bronchial epithelial cells and in a subset of human non-small-cell lung cancer cell lines. Iloprost-impregnated chow fed to wild-type mice resulted in elevated lung macrophages and decreased lung tumor formation. Transgenic animals with lung-specific PPARγ overexpression also developed fewer lung tumors. This reduction was not enhanced by administration of supplemental iloprost. These studies indicate that PPARγ is a critical target for prostacyclin-mediated lung cancer chemoprevention and may also have therapeutic activity.In the United States, lung cancer continues to be the leading cause of cancer death in both men and women, and worldwide the lung cancer epidemic will result in millions of cases yearly (1). Whereas tobacco abstinence and smoking cessation are the critical first steps in reducing lung cancer rates, the majority of U.S. lung cancers are diagnosed in former smokers. To date, no effective chemopreventive agents have been discovered. The large at-risk population (current and former smokers) and poor 5-year lung cancer survival rates (2) underscore the need for a better understanding of chemopreventive mechanisms and effective agents.Prostaglandins play an important role in lung tumorigenesis, and prostaglandin manipulation has been investigated for lung cancer chemoprevention. Cyclooxygenase (COX) inhibition decreases levels of prostaglandins, and large epidemiologic surveys have shown fewer lung cancers in "frequent aspirin users" (3). Human trials evaluating COX inhibition and lung cancer chemoprevention are currently being conducted, but conflicting data in murine studies evaluating the role of nonspecific COX or selective COX-2 inhibition make interpretation of these results difficult. Studies using nonselective COX inhibitors have shown inhibition of lung tumorigenesis in mice (4, 5). However, mice receiving celecoxib (a selective COX-2 inhibitor) showed reduced pulmonary inflammation, but no differences in tumor multiplicity, and an actual increase in tumor size after exposure to an initiator-promoter model of lung tumorigen...
Squamous cell carcinoma (SCC) and pre-malignant endobronchial lesions have been difficult to study in murine models. In this report, we evaluate the topical N-nitroso-tris-chloroethylurea (NTCU) murine SCC model, determine the extent to which resulting pre-malignant airway dysplasia develops, discuss clinicopathologic grading criteria in lesion progression, and confirm that immunohistochemical (IHC) staining patterns are consistent with those observed in human endobronchial dysplasia and SCC. Male and female FVB mice were treated biweekly with topical NTCU (4, 8, or 40mM) or vehicle for 32 weeks. Following sacrifice, squamous cell lesions were enumerated and categorized into the following groups: flat atypia, low-grade dysplasia, high-grade dysplasia, and invasive SCC. The 40mM NTCU concentration produced the entire spectrum of premalignant dysplasias and squamous cell carcinomas, but was associated with poor survival. Concentrations of 4mM and 8mM NTCU were better tolerated and produced only significant levels of flat atypia. Squamous origin of the range of observed lesions was confirmed with IHC staining for cytokeratin 5/6, p63, thyroid transcription factor-1 (TTF-1), and Napsin-A. This study demonstrates that topical application of high dose NTCU produces endobronchial pre-malignant lesions with classic squamous characteristics and should allow for improved pre-clinical evaluation of potential chemopreventive agents.
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