The online version of this article (doi:10.1186/1476-4598-11-4) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
PB carried out the mouse in vivo study including NNK injection, weekly NTHi exposure, and lung tissue extraction, and participated in preparing the figures and drafting the manuscript. CVP carried out the histopathology examination and analysis of the lung tissues and participated in preparing the figures. TM participated in the mouse colony maintenance, genotyping, and lung tissue extraction. BFD participated in the design of the study and the drafting the manuscript. RL conceived of the study, and participated in its design and coordination and helped to draft the manuscript. SJM participated in the design of the study, assessed lung tumor burden and inflammation, performed the statistical analysis, and participated in preparing the figures and drafting the manuscript. All authors read and approved the final manuscript.
Although cigarette smoking is the principal cause of lung carcinogenesis, chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, has been identified as an independent risk factor for lung cancer. Bacterial colonization, particularly with non-typeable Haemophilus influenzae (NTHi), has been implicated as a cause of airway inflammation in COPD besides cigarette smoke. Accordingly, we hypothesized that lung cancer promotion may occur in a chronic inflammatory environment in the absence of concurrent carcinogen exposure.
Herein, we investigated the effects of bacterial-induced COPD-like inflammation and tobacco carcinogen-enhanced tumorigenesis/inflammation in the retinoic acid inducible G protein coupled receptor knock out mouse model (Gprc5a-/- mouse) characterized by late-onset, low multiplicity tumor formation. Three-month-old Gprc5a-/- mice received 4 intraperitoneal injections of the tobacco-specific carcinogen, NNK, followed by weekly exposure to aerosolized NTHi lysate for 6 months. The numbers of inflammatory cells in the lungs and levels of several inflammatory mediators were increased in Gprc5a-/- mice treated with NTHi alone, and even more so in mice pretreated with NNK followed by NTHi. The incidence of spontaneous lung lesions in the Gprc5a-/- mice was low, but NTHi exposure led to enhanced development of hyperplastic lesions. Gprc5a-/- mice exposed to NNK alone developed multiple lung tumors, while NTHi exposure increased the number of hyperplastic foci 6-fold and the tumor multiplicity 2-fold. This was associated with increased microvessel density and HIF-1α expression.
We conclude that chronic extrinsic lung inflammation induced by bacteria alone or in combination with NNK enhances lung tumorigenesis in Gprc5a-/- mice.
Authors’ original file for figure 112943_2011_981_MOESM1_ESM.tiff
Authors’ original file for figure 212943_2011_981_MOESM2_ESM.tiff
Authors’ original file for figure 312943_2011_981_MOESM3_ESM.tiff
Authors’ original file for figure 412943_2011_981_MOESM4_ESM.tiff
Authors’ original file for figure 512943_2011_981_MOESM5_ESM.tiff
Stellman SD, Takezaki T, Wang L, Chen Y, Citron ML, Djordjevic MV, Harlap S, Muscat JE, Neugut AI, Wynder EL: Smoking and lung cancer risk in American and Japanese men: an international case-control study. Cancer Epidemiol Biomarkers Prev. 2001, 10: 1193-1199. PubMed
Schottenfield D: Etiology and epidemiology of lung cancer. Lung cancer: Principles and Practice. Edited by: Pass HIMJBJDHTATMJD. 2000, 367-388. Philadelphia: Lippincott, Williams and Wilkins,
Moghaddam SJ, Clement CG, De la Garza MM, Zou X, Travis EL, Young HW, Evans CM, Tuvim MJ, Dickey BF: Haemophilus influenzae lysate induces aspects of the chronic obstructive pulmonary disease phenotype. Am J Respir Cell Mol Biol. 2008, 38: 629-638. 10.1165/rcmb.2007-0366OC PubMedCentralCrossRefPubMed
Ochoa CE, Mirabolfathinejad SG, Ruiz VA, Evans SE, Gagea M, Evans CM, Dickey BF, Moghaddam SJ: Interleukin 6, but not T helper 2 cytokines, promotes lung carcinogenesis. Cancer Prev Res (Phila). 2011, 4: 51-64. 10.1158/1940-6207.CAPR-10-0180. CrossRef
Imtiyaz HZ, Simon MC: Hypoxia-Inducible Factors as Essential Regulators of Inflammation. Curr Top Microbiol Immunol. 2010,
Borm PJ, Driscoll K: Particles, inflammation and respiratory tract carcinogenesis. Toxicol Lett. 1996, 88: 109-113. PubMed
Deng J, Fujimoto J, Ye XF, Men TY, Van Pelt CS, Chen YL, Lin XF, Kadara H, Tao Q, Lotan D: Knockout of the tumor suppressor gene Gprc5a in mice leads to NF-kappaB activation in airway epithelium and promotes lung inflammation and tumorigenesis. Cancer Prev Res (Phila). 2010, 3: 424-437. 10.1158/1940-6207.CAPR-10-0032. CrossRef
Shin DH, Li SH, Yang SW, Lee BL, Lee MK, Park JW: Inhibitor of nuclear factor-kappaB alpha derepresses hypoxia-inducible factor-1 during moderate hypoxia by sequestering factor inhibiting hypoxia-inducible factor from hypoxia-inducible factor 1alpha. FEBS J. 2009, 276: 3470-3480. 10.1111/j.1742-4658.2009.07069.x CrossRefPubMed
Stathopoulos GT, Sherrill TP, Cheng DS, Scoggins RM, Han W, Polosukhin VV, Connelly L, Yull FE, Fingleton B, Blackwell TS: Epithelial NF-kappaB activation promotes urethane-induced lung carcinogenesis. Proc Natl Acad Sci USA. 2007, 104: 18514-18519. 10.1073/pnas.0705316104 PubMedCentralCrossRefPubMed
Ye P, Rodriguez FH, Kanaly S, Stocking KL, Schurr J, Schwarzenberger P, Oliver P, Huang W, Zhang P, Zhang J: Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J Exp Med. 2001, 194: 519-527. 10.1084/jem.194.4.519 PubMedCentralCrossRefPubMed
Di Stefano A, Caramori G, Gnemmi I, Contoli M, Vicari C, Capelli A, Magno F, D'Anna SE, Zanini A, Brun P: T helper type 17-related cytokine expression is increased in the bronchial mucosa of stable chronic obstructive pulmonary disease patients. Clin Exp Immunol. 2009, 157: 316-324. 10.1111/j.1365-2249.2009.03965.x PubMedCentralCrossRefPubMed
Nikitin AY, Alcaraz A, Anver MR, Bronson RT, Cardiff RD, Dixon D, Fraire AE, Gabrielson EW, Gunning WT, Haines DC: Classification of proliferative pulmonary lesions of the mouse: recommendations of the mouse models of human cancers consortium. Cancer Res. 2004, 64: 2307-2316. 10.1158/0008-5472.CAN-03-3376 CrossRefPubMed
- Enhancement of lung tumorigenesis in a Gprc5a Knockout mouse by chronic extrinsic airway inflammation
Carolyn Van Pelt
Burton F Dickey
Seyed Javad Moghaddam
- BioMed Central
Neu im Fachgebiet Onkologie
Mail Icon II