Pulmonary prostacyclin synthase overexpression chemoprevents tobacco smoke lung carcinogenesis in mice

Robert L. Keith, York E. Miller, Tyler M. Hudish, Carlos E. Girod, Sylk Sotto-Santiago, Wilbur A. Franklin, Raphael A. Nemenoff, Thomas H. March, S. Patrick Nana-Sinkam, Mark W. Geraci

Research output: Contribution to journalArticle

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Abstract

Increased pulmonary production of prostaglandin I2 (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 lung-specific 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 prostagiandin levels at the time of sacrifice revealed significantly elevated prostaglandin I2 levels in the transgenic animals, coupled with significantly decreased prostaglandin E2 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.

Original languageEnglish (US)
Pages (from-to)5897-5904
Number of pages8
JournalCancer Research
Volume64
Issue number16
DOIs
StatePublished - Aug 15 2004
Externally publishedYes

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Smoke
Tobacco
Carcinogenesis
Lung
Epoprostenol
Neoplasms
Bronchiolitis
Genetically Modified Animals
Incidence
Alveolar Epithelial Cells
Gene Expression
Cytochrome P-450 CYP2E1
Chemoprevention
Prostaglandin-Endoperoxide Synthases
prostacyclin synthetase
Transgenes
Dinoprostone
Tobacco Products
Transgenic Mice
Prostaglandins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Keith, R. L., Miller, Y. E., Hudish, T. M., Girod, C. E., Sotto-Santiago, S., Franklin, W. A., ... Geraci, M. W. (2004). Pulmonary prostacyclin synthase overexpression chemoprevents tobacco smoke lung carcinogenesis in mice. Cancer Research, 64(16), 5897-5904. https://doi.org/10.1158/0008-5472.CAN-04-1070

Pulmonary prostacyclin synthase overexpression chemoprevents tobacco smoke lung carcinogenesis in mice. / Keith, Robert L.; Miller, York E.; Hudish, Tyler M.; Girod, Carlos E.; Sotto-Santiago, Sylk; Franklin, Wilbur A.; Nemenoff, Raphael A.; March, Thomas H.; Nana-Sinkam, S. Patrick; Geraci, Mark W.

In: Cancer Research, Vol. 64, No. 16, 15.08.2004, p. 5897-5904.

Research output: Contribution to journalArticle

Keith, RL, Miller, YE, Hudish, TM, Girod, CE, Sotto-Santiago, S, Franklin, WA, Nemenoff, RA, March, TH, Nana-Sinkam, SP & Geraci, MW 2004, 'Pulmonary prostacyclin synthase overexpression chemoprevents tobacco smoke lung carcinogenesis in mice', Cancer Research, vol. 64, no. 16, pp. 5897-5904. https://doi.org/10.1158/0008-5472.CAN-04-1070
Keith RL, Miller YE, Hudish TM, Girod CE, Sotto-Santiago S, Franklin WA et al. Pulmonary prostacyclin synthase overexpression chemoprevents tobacco smoke lung carcinogenesis in mice. Cancer Research. 2004 Aug 15;64(16):5897-5904. https://doi.org/10.1158/0008-5472.CAN-04-1070
Keith, Robert L. ; Miller, York E. ; Hudish, Tyler M. ; Girod, Carlos E. ; Sotto-Santiago, Sylk ; Franklin, Wilbur A. ; Nemenoff, Raphael A. ; March, Thomas H. ; Nana-Sinkam, S. Patrick ; Geraci, Mark W. / Pulmonary prostacyclin synthase overexpression chemoprevents tobacco smoke lung carcinogenesis in mice. In: Cancer Research. 2004 ; Vol. 64, No. 16. pp. 5897-5904.
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abstract = "Increased pulmonary production of prostaglandin I2 (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 lung-specific 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 prostagiandin levels at the time of sacrifice revealed significantly elevated prostaglandin I2 levels in the transgenic animals, coupled with significantly decreased prostaglandin E2 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.",
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