Enhancement of lung tumorigenesis in a Gprc5a Knockout mouse by chronic extrinsic airway inflammation
- Peter Barta1,
- Carolyn Van Pelt2,
- Taoyan Men1,
- Burton F Dickey3,
- Reuben Lotan^1 and
- Seyed Javad Moghaddam3Email author
© Barta et al; licensee BioMed Central Ltd. 2012
Received: 7 December 2011
Accepted: 12 January 2012
Published: 12 January 2012
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.
Keywordslung cancer inflammation COPD Gpcr5a NTHi
Worldwide, lung cancer remains the leading cause of cancer death in both men and women, even though an extensive list of modifiable risk factors has long been identified . Cigarette smoking is the principal cause of lung carcinogenesis . However several studies have found that smokers with chronic obstructive pulmonary disease (COPD) have an increased risk of lung cancer (3 to 10 fold) compared to smokers with comparable cigarette exposure but without COPD [3, 4]. It has also been shown that increased lung cancer mortality is associated with a history of COPD, even among persons who had never been active smokers .
The pooled global prevalence of COPD in adults 40 years or older is 9%, and it is a leading cause of morbidity and mortality in the United States . Histopathologic studies have clearly demonstrated lung inflammation in COPD . Smoking also causes most cases of COPD , however, among smokers with COPD, inflammation persists and lung function continues to deteriorate even following withdrawal of cigarette smoke . These facts suggest that the later phase of lung carcinogenesis may occur in a chronic inflammatory environment in the absence of concurrent carcinogen exposure.
We have previously established a COPD-like mouse model of airway inflammation induced by repetitive exposure to an aerosolized lysate of non-typeable Haemophilus influenzae (NTHi) . NTHi is the most common bacterial colonizer of airways in COPD patients [10, 11], present in the airways of 30% of COPD patients measured at a single point in time, and in more than 50% of COPD patients followed longitudinally . We have shown that NTHi-induced COPD-like inflammation enhances lung tumorigenesis in a mouse model of lung cancer induced by airway epithelial expression of an oncogene (K-ras) . Importantly, we and others have shown that there is a clear specificity for the nature of inflammation in lung cancer promotion, because induction of asthma-like (Th2 type) airway inflammation using weekly exposure to ovalbumin (OVA) aerosol in the same K-ras mutant mouse model  or in the urethane-induced lung cancer mouse model  did not result in a significant difference in lung surface tumor number.
Because tobacco smoking is a major cause of lung cancer, and smokers with COPD have the highest risk of lung cancer, it is also important to define how bacterial-induced COPD-like airway inflammation and tobacco carcinogen exposure alter lung tumorigenesis in mice. In the current study we have addressed this question using a tobacco-specific carcinogen exposure followed by an NTHi exposure in a newly developed genetic mouse model of lung cancer induced by lack of a tumor suppressor gene. This mouse model is based on the knockout of the retinoic acid inducible G protein coupled receptor Gprc5a gene, which leads to late-onset, low multiplicity lung tumor formation as previously described . This differs substantially from the model we have used previously (the K-ras oncogene induced mouse model of lung cancer), and better emulates the typical course of lung cancer development in the setting of COPD in humans who have smoked cigarettes and become chronically colonized with bacteria. We found that Gprc5a-/- mice treated with NTHi alone develop chronic COPD-like inflammation and exhibit a several fold increase in the incidence of premalignant lesions. Furthermore, NTHi strongly enhanced lung tumor multiplicity in mice pretreated with the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).
Effect of NNK and NTHi on lung inflammation
Inflammatory mediators detected in BALF collected the day after the last treatment
13.4 ± 1.5
67.9 ± 9.5
59.4 ± 2.5
48.5 ± 5.2
4.1 ± 0.6
18.5 ± 1.2
21.2 ± 2.4
52.5 ± 4.9
1.7 ± 0.4
4.1 ± 0.3
60.8 ± 17.5
128.3 ± 20.5
8.8 ± 1.4
95.2 ± 11.7
59.1 ± 5.4
36.1 ± 3.2
0.4 ± 0.1
1.1 ± 0.1
46.9 ± 1.9
19.9 ± 0.3
4.7 ± 1.3
8.8 ± 1.8
9.7 ± 0.4
70.9 ± 10.6
1.3 ± 0.3
2.7 ± 1.1
7.6 ± 0.7
13.8 ± 2.6
12.9 ± 0.3
22.8 ± 6.8
19.3 ± 1.1
44.3 ± 1.7
Effect of NNK and NTHi on lung tumor progression
Effect of NNK and NTHi on microvascular density and HIF-1α expression
The likelihood of developing lung cancer within 10 years is 3-fold greater in patients with mild to moderate COPD and 10-fold greater in patients with severe COPD compared to smokers with normal lung function . COPD is thought to be caused by the lung paranchymal response to inflammation from cigarette smoke and bacterial colonization of smoke-injured airways [10, 20]. These epidemiologic data suggest that chronic airway inflammation caused by tobacco smoke and microbial infection promote lung carcinogenesis [21, 22], and that lung cancer risk is positively associated with the severity and duration of inflammation . However, while these data underlie the relationships, they do not establish causal links which are addressed in this study using a novel mouse model of lung carcinogenesis.
Tumor cells themselves produce various cytokines and chemokines that attract leukocytes (intrinsic inflammation). The inflammatory component of a developing neoplasm may include a diverse leukocyte population including neutrophils, dendritic cells, macrophages, and lymphocytes, all of which are capable of producing an array of cytokines, cytotoxic mediators including reactive oxygen species, serine and cysteine proteases, and matrix metalloproteinases (MMPs) [24, 25]. Sustained cell proliferation in this environment rich in inflammatory cells, growth factors, activated stroma, and DNA-damage-promoting agents potentiates neoplastic risk [24, 26]. We have previously shown that the loss of the tumor suppressor gene Gprc5a in mouse lung epithelial cells results in expression of various cytokines and chemokines, followed by recruitment of inflammatory cells into the lung tumor microenvironment . Furthermore, increased activation of NF-κB in the Gprc5a-/- mouse lungs has been implicated in the creation of an inflammatory and proliferative microenvironment . More recently, we have demonstrated that exposure of the Gprc5a knockout mice to the tobacco-specific carcinogen NNK enhances lung tumorigenesis . In the present study, we have shown that extrinsic inflammation caused by bacterial infection and carcinogen exposure emulating COPD lung microenvironment, can further promote tumorigenesis in this mouse model. We previously showed the role of bacterial-induced COPD-like inflammation in promotion of lung tumorigenesis in an oncogenic K-ras induced mouse model of lung cancer . Here we showed the role of bacterial-induced COPD-like inflammation in a background of tobacco carcinogen exposure in lung cancer promotion and progression in a mouse model with lack of Gprc5a activity. Deletion of Gprc5a, which is expressed preferentially in lung tissue, predisposes mice to develop spontaneous lung tumors , but the tumorigenesis process in the Gprc5a-/- mouse takes 1 to 2 years with low multiplicity. Even with exposure to NNK , the time to tumor development is slow (12 months). This is in contrast with the rapid development and high multiplicity of tumors in K-ras mutant mouse model . Therefore, the Gprc5a knockout mouse model emulates better the typical course of lung cancer development in the setting of COPD in humans who have smoked cigarette and became chronically colonized with bacteria.
Cigarette smoke contains ~4,000 chemicals, of which ~60 have been identified as carcinogens . Of these NNK is the most potent carcinogen in laboratory animals and has therefore been implicated as a significant cause of tobacco-associated cancers including lung cancer . Activating mutations of K-ras, which are found in 30%-50% of lung adenocarcinoma (AC), are one of the most common genetic alterations associated with tobacco exposure . Within days after NNK administration, K-ras becomes mutated and activated in alveolar type II pneumocytes and bronchiolar Clara cells, the putative cells from which lung AC originate [31, 32]. However, in the present study, we showed that NNK exposure of Gprc5a knockout mice also results in increased levels of inflammatory mediators and recruitment of inflammatory cells into the lungs, which leads to lung tumor promotion. This is in agreement with the recent finding of a lung cancer promoting effect for smoke-induced inflammation independent of its direct mutagenesis effect in a K-ras mutant mouse model . Chronic NTHi exposure in Gprc5a-/- mice resulted in increased levels of inflammatory mediators followed by recruitment of inflammatory cells into the lungs (COPD-like inflammation) and lung cancer promotion, similar to what we have previously described in our K-ras induced mouse model . The highest levels of inflammation and tumor promotion were seen in Gprc5a-/- mice exposed to both NNK and NTHi, indicating an additive role for smoke- and bacterial-induced inflammation in progression from COPD to lung cancer.
Sustained angiogenesis is one of the hallmarks of cancer , and it is required for tumor promotion. We have also found increased microvessel density in response to NTHi-induced inflammation. This was associated with increased expression of HIF-1α which controls inflammation , and activates the transcription of genes involved in crucial aspects of cancer biology, including angiogenesis . NF-κB is a critical transcriptional activator of HIF-1α activity and is required for HIF-1α protein accumulation during hypoxia [35–37]. Activation of NF-κB, a hallmark of inflammatory responses, is frequently detected in COPD patients , smokers  and tumors . NF-κB is essential for promoting inflammation-associated cancers, and its inactivation decreases tumor multiplicity and delays cancer progression [41–43]. In the lung there are also a limited number of studies which show that NF-κB inhibition suppresses lung cancer in mouse [44, 45]. We have previously found NF-κB activation in the lungs of wild type (WT) mice , Gprc5a-/- mice , and in mice with mutant K-ras exposed to NTHi [13, 46]. We have also shown increased level of HIF-1α transcript in gene expression analysis of whole lung from WT, and mutant K-ras mice after NTHi exposure . In this study, we found that a single exposure to aerosolized NTHi was sufficient to increase NF-κB activation five-fold in the lung of WT and Gprc5a-/- mice (data not shown), along with increased expression of HIF-1α (Figure 5). All together these data suggest a role for NF-κB in lung cancer promotion in the Gprc5a-/- mice in response to bacterial induced inflammation through activation of the HIF-1α pathway and its downstream angiogenic signals.
One of the events downstream of NF-κB activation is production of various cytokines and chemokines (e.g. IL-6, and IL-17) that attract leukocytes , which results in enhanced tumor progression, cancer cell growth and spread, angiogenesis, invasion and tumor immunosuppression [24, 25]. We have found significantly increased level of IL-6 and IL-17 in BALF after NTHi exposure alone or in combination with NNK treatment (table 1). We have previously shown an essential role for IL-6 in promotion of lung cancer by airway inflammation . IL-6 is required for differentiation of Th17 cells from naïve T cells, which mainly produce IL-17 [47, 48]. IL-17 binds to the IL-17 receptor (IL-17R), and IL-17R signaling is required for lung CXC chemokine expression and neutrophil recruitment . In addition to the traditional T helper 1 (Th1) response (IFN-γ) in COPD, recent developments in cytokine biology imply that COPD might be better explained by the Th17 phenotype [50, 51]. These are consistent with our finding after inducing COPD-like inflammation by NTHi exposure (table 1 and Figure 2A). NNK exposure may induce a type of immune response (T regulatory response) which suppresses the anti-tumoral immune response (CD8 T cell, and Th1 responses) and meanwhile balances the Th17 response toward an effective pro-tumoral response.
During immune responses, neutrophils are among the first cells to arrive at sites of inflammation. This is similar to our finding of significant neutrophil recruitment after NTHi exposure in Gprc5a-/- mice (Figure 2A). An increased number of tumor-associated neutrophils (TANs) was linked to poorer outcome in patients with bronchioloalveolar carcinoma . Neutrophils were present within the alveolar airspaces and within the tumor parenchyma during neoplastic development in a urethane-induced mouse model of lung cancer . Using a K-ras induced mouse model, study has shown that TANs were involved in lung tumorigenesis by the production of elastase . We have also shown an indirect anti-tumoral effect for curcumin through inhibition of neutrophil recruitment secondary to suppression of neutrophil chemoattractant (KC) in our K-ras induced lung cancer model .
In conclusion, we propose that exposure of the airway to smoke and microbial products induces inflammation, which promotes the development of lung cancer. This is associated with activation of NF-κB, release of inflammatory mediators, recruitment of innate (neutrophil, and macrophages) and adaptive inflammatory cells, and activation of HIF-1α mediated angiogenesis. This will provide the basis for preclinical testing and rationally directed chemopreventive strategies to test the efficacy of anti-inflammatory and anti-bacterial agents targeting these signals in preventing carcinogenesis in patients at high risk for tumor development and early stage cancer.
Animals and treatment
Gprc5a knockout mice (Gprc5a-/- mice) were generated in a mixed background of 129sv × C57BL/6 as previously described . The mice were maintained according to a protocol approved by the MD Anderson Cancer Center Institutional Animal Care and Use Committee in the specific pathogen-free animal facility, which is approved by the American Association for Accreditation of Laboratory Animal Care and is operated in accordance with current regulations and standards of the US Department of Agriculture and the Department of Health and Human Services. Mice were monitored daily for evidence of disease or death. Three-month-old Gprc5a-/- mice (n = 20) received 4 weekly i.p. injections of NNK (104 mg/kg of body weight) (Midwest Research Institute, Kansas City, MO) dissolved in saline solution (0.9% NaCl) or saline alone (n = 20), followed by weekly inhalation of the UV-killed lysate of NTHi (n = 10) or saline (n = 10) from the age of 6 to12 months (Figure 1). Briefly, a lysate of NTHi strain 12 was prepared as previously described . The protein concentration was adjusted to 2.5 mg/ml in phosphate buffered saline (PBS), and the lysate was frozen in 10 ml aliquots at -80°C. To deliver the lysate to mice by aerosol, a thawed aliquot was placed in an AeroMist CA-209 nebulizer (CIS-US, Bedford, MA) driven by 10 l/min of room air supplemented with 5% CO2 for 20 minutes.
Assessment of lung tumor burden and inflammation
One day after the last NTHi exposure, animals were euthanized by i.p. injection of a lethal dose of avertin (Sigma-Aldrich, St. Louis, MO). Lung surface lesion numbers were counted (any macroscopic lesion, tumoral or non-tumoral, seen with the naked eye on the lung surface), then the lungs were prepared for histological analysis as described below. In some mice (n = 5), BALF was obtained by sequentially instilling and collecting two aliquots of 1 ml PBS through a tracheostomy cannula. Total leukocyte count was determined using a hemacytometer, and cell populations were determined after cytocentrifugation of 300 μl of BALF followed by Wright-Giemsa staining. The remaining BALF (~1.4 ml) was centrifuged at 1,250 × g for 10 min, and supernatants were collected and stored at -70°C. Cytokine concentrations were measured in duplicate by multiplexed sandwich ELISA using SearchLight Proteome Arrays (Aushon Biosystems, Billerica, MA).
The tracheas of euthanized mice were cannulated with PE-50 tubing and sutured into place. The lungs were perfused in situ with PBS via the right cardiac ventricle, then infused with 10% buffered formalin (Sigma-Aldrich), removed and placed in 10% buffered formalin for 18 h. Tissues then were transferred to 75% ethanol, embedded in paraffin and sectioned at 5-μm thickness. Sections were dried at 60°C for 15 min, and then were deparaffinized. Hematoxylin and eosin (H&E) staining was performed by incubating the tissues in Harris hematoxylin (Sigma-Aldrich) followed by serial eosin and graded ethanol steps. Three H&E sections, each 600 μm apart, were analyzed blindly by a veterinary pathologist for proliferative lesions, tumor (adenoma + adenocarcinoma) multiplicity, incidence, inflammatory infiltrations and overall inflammation grade according to the recommendations of the Mouse Models of Human Cancer Consortium . The severity of inflammatory lesions of the lungs were scored from 1 to 4 as follows: grade 1 - minimal, lesions affect less than 10% of tissue; grade 2 - mild, lesions affect 10-20% of tissue; grade 3 - moderate, lesions affect 21-40% of tissue; and grade 4 - marked or severe, lesions affect 41-100% of the tissue. Some sections (5 μm) from NNK- and NNK/NTHi-treated groups were labeled with anti-CD105 antibody (Biocare Medical LLC., Concord, CA) after antigen retrieval procedure for 20 min at 95°C in Tris-EDTA buffer, pH 9.0, and HIF-1α antibody (Novus Biologicals, Littleton, CO, USA). Slides were then incubated with secondary antibody, exposed to horseradish peroxidase-labeled streptavidin (Vector, Burlingame, CA), developed with diaminobenzidine (Vector, Burlingame, CA), and counterstained with hematoxylin (Sigma-Aldrich).
Summary statistics for cell counts in BALF and tumor counts were computed within treatment groups, and analysis of variance with adjustment for multiple comparisons was performed to examine the differences between the mean cell counts and tumor count of the control group and each of the NTHi and or NTHi/NNK treatment groups. Differences were considered significant for P < 0.05.
List of abbreviations
chronic obstructive pulmonary disease
phosphate buffered saline
bronchoalveolar lavage fluid
hematoxylin and eosin
tumor-associated neutrophils: NF-κB: nuclear factor kappa B
hypoxia inducible factor 1α.
We thank Ms. Dafna Lotan, and Ms. Seyedeh Golsar Mirabolfathinejad for their technical assistance in the completion of this project. This study was supported by the Samuel Waxman Cancer Research Foundation, by the Jimmy Lane Hewlett Fund for Lung Cancer Research, and by the Cancer Center Support Grant P30 CA16672 (Veterinary Medicine Core).
- Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ: Cancer statistics. CA Cancer J Clin. 2009, 59: 225-249. 10.3322/caac.20006View ArticlePubMedGoogle Scholar
- 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.PubMedGoogle Scholar
- 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,Google Scholar
- Mannino DM, Aguayo SM, Petty TL, Redd SC: Low lung function and incident lung cancer in the United States: data From the First National Health and Nutrition Examination Survey follow-up. Arch Intern Med. 2003, 163: 1475-1480. 10.1001/archinte.163.12.1475View ArticlePubMedGoogle Scholar
- Turner MC, Chen Y, Krewski D, Calle EE, Thun MJ: Chronic obstructive pulmonary disease is associated with lung cancer mortality in a prospective study of never smokers. Am J Respir Crit Care Med. 2007, 176: 285-290. 10.1164/rccm.200612-1792OCView ArticlePubMedGoogle Scholar
- Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS, Mannino DM: Global burden of COPD: systematic review and meta-analysis. Eur Respir J. 2006, 28: 523-532. 10.1183/09031936.06.00124605View ArticlePubMedGoogle Scholar
- Jeffery PK: Comparison of the structural and inflammatory features of COPD and asthma. Giles F. Filley Lecture. Chest. 2000, 117: 251S-260S. 10.1378/chest.117.5_suppl_1.251SView ArticlePubMedGoogle Scholar
- Shapiro SD: End-stage chronic obstructive pulmonary disease: the cigarette is burned out but inflammation rages on. Am J Respir Crit Care Med. 2001, 164: 339-340.View ArticlePubMedGoogle Scholar
- 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.2007-0366OCPubMed CentralView ArticlePubMedGoogle Scholar
- King PT, Hutchinson PE, Johnson PD, Holmes PW, Freezer NJ, Holdsworth SR: Adaptive immunity to nontypeable Haemophilus influenzae. Am J Respir Crit Care Med. 2003, 167: 587-592. 10.1164/rccm.200207-728OCView ArticlePubMedGoogle Scholar
- Murphy TF: Haemophilus influenzae in chronic bronchitis. Semin Respir Infect. 2000, 15: 41-51. 10.1053/srin.2000.0150041View ArticlePubMedGoogle Scholar
- Sethi S, Murphy TF: Bacterial infection in chronic obstructive pulmonary disease in 2000: a state-of-the-art review. Clin Microbiol Rev. 2001, 14: 336-363. 10.1128/CMR.14.2.336-363.2001PubMed CentralView ArticlePubMedGoogle Scholar
- Moghaddam SJ, Li H, Cho SN, Dishop MK, Wistuba II, Ji L, Kurie JM, Dickey BF, DeMayo FJ: Promotion of lung carcinogenesis by chronic obstructive pulmonary disease-like airway inflammation in a K-ras-induced mouse model. Am J Respir Cell Mol Biol. 2009, 40: 443-453.PubMed CentralView ArticlePubMedGoogle Scholar
- 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.View ArticleGoogle Scholar
- Doris K, Karabela SP, Kairi CA, Simoes DC, Roussos C, Zakynthinos SG, Kalomenidis I, Blackwell TS, Stathopoulos GT: Allergic inflammation does not impact chemical-induced carcinogenesis in the lungs of mice. Respir Res. 2010, 11: 118- 10.1186/1465-9921-11-118PubMed CentralView ArticlePubMedGoogle Scholar
- Tao Q, Fujimoto J, Men T, Ye X, Deng J, Lacroix L, Clifford JL, Mao L, Van Pelt CS, Lee JJ: Identification of the retinoic acid-inducible Gprc5a as a new lung tumor suppressor gene. J Natl Cancer Inst. 2007, 99: 1668-1682. 10.1093/jnci/djm208View ArticlePubMedGoogle Scholar
- Ribatti D, Crivellato E: Immune cells and angiogenesis. J Cell Mol Med. 2009, 13: 2822-2833. 10.1111/j.1582-4934.2009.00810.xPubMed CentralView ArticlePubMedGoogle Scholar
- Semenza GL: Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003, 3: 721-732. 10.1038/nrc1187View ArticlePubMedGoogle Scholar
- Imtiyaz HZ, Simon MC: Hypoxia-Inducible Factors as Essential Regulators of Inflammation. Curr Top Microbiol Immunol. 2010,Google Scholar
- Barnes PJ: New concepts in chronic obstructive pulmonary disease. Annu Rev Med. 2003, 54: 113-129. 10.1146/annurev.med.54.101601.152209View ArticlePubMedGoogle Scholar
- Dhala A, Pinsker K, Prezant DJ: Respiratory health consequences of environmental tobacco smoke. Med Clin North Am. 2004, 88: 1535-52. xi, 10.1016/j.mcna.2004.06.005View ArticlePubMedGoogle Scholar
- Philip M, Rowley DA, Schreiber H: Inflammation as a tumor promoter in cancer induction. Semin Cancer Biol. 2004, 14: 433-439. 10.1016/j.semcancer.2004.06.006View ArticlePubMedGoogle Scholar
- Borm PJ, Driscoll K: Particles, inflammation and respiratory tract carcinogenesis. Toxicol Lett. 1996, 88: 109-113.PubMedGoogle Scholar
- Coussens LM, Werb Z: Inflammation and cancer. Nature. 2002, 420: 860-867. 10.1038/nature01322PubMed CentralView ArticlePubMedGoogle Scholar
- Lin EY, Pollard JW: Role of infiltrated leucocytes in tumour growth and spread. Br J Cancer. 2004, 90: 2053-2058. 10.1038/sj.bjc.6601705PubMed CentralView ArticlePubMedGoogle Scholar
- Balkwill F, Charles KA, Mantovani A: Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell. 2005, 7: 211-217. 10.1016/j.ccr.2005.02.013View ArticlePubMedGoogle Scholar
- 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.View ArticleGoogle Scholar
- Fujimoto J, Kadara H, Men T, van Pelt C, Lotan D, Lotan R: Comparative functional genomics analysis of NNK tobacco-carcinogen induced lung adenocarcinoma development in Gprc5a-knockout mice. PLoS ONE. 2010, 5: e11847- 10.1371/journal.pone.0011847PubMed CentralView ArticlePubMedGoogle Scholar
- Schuller HM: Mechanisms of smoking-related lung and pancreatic adenocarcinoma development. Nat Rev Cancer. 2002, 2: 455-463. 10.1038/nrc824View ArticlePubMedGoogle Scholar
- Rodenhuis S, Slebos RJ: The ras oncogenes in human lung cancer. Am Rev Respir Dis. 1990, 142: S27-S30.View ArticlePubMedGoogle Scholar
- Bauer AK, Malkinson AM, Kleeberger SR: Susceptibility to neoplastic and non-neoplastic pulmonary diseases in mice: genetic similarities. Am J Physiol Lung Cell Mol Physiol. 2004, 287: L685-L703. 10.1152/ajplung.00223.2003View ArticlePubMedGoogle Scholar
- Rehm S, Devor DE, Henneman JR, Ward JM: Origin of spontaneous and transplacentally induced mouse lung tumors from alveolar type II cells. Exp Lung Res. 1991, 17: 181-195. 10.3109/01902149109064410View ArticlePubMedGoogle Scholar
- Takahashi H, Ogata H, Nishigaki R, Broide DH, Karin M: Tobacco smoke promotes lung tumorigenesis by triggering IKKbeta- and JNK1-dependent inflammation. Cancer Cell. 2010, 17: 89-97. 10.1016/j.ccr.2009.12.008PubMed CentralView ArticlePubMedGoogle Scholar
- Hanahan D, Weinberg RA: The hallmarks of cancer. Cell. 2000, 100: 57-70. 10.1016/S0092-8674(00)81683-9View ArticlePubMedGoogle Scholar
- Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG, Karin M: NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature. 2008, 453: 807-811. 10.1038/nature06905PubMed CentralView ArticlePubMedGoogle Scholar
- van Uden P, Kenneth NS, Rocha S: Regulation of hypoxia-inducible factor-1alpha by NF-kappaB. Biochem J. 2008, 412: 477-484. 10.1042/BJ20080476PubMed CentralView ArticlePubMedGoogle Scholar
- 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.xView ArticlePubMedGoogle Scholar
- Di Stefano A, Caramori G, Oates T, Capelli A, Lusuardi M, Gnemmi I, Ioli F, Chung KF, Donner CF, Barnes PJ: Increased expression of nuclear factor-kappaB in bronchial biopsies from smokers and patients with COPD. Eur Respir J. 2002, 20: 556-563. 10.1183/09031936.02.00272002View ArticlePubMedGoogle Scholar
- Schabath MB, Delclos GL, Martynowicz MM, Greisinger AJ, Lu C, Wu X, Spitz MR: Opposing effects of emphysema, hay fever, and select genetic variants on lung cancer risk. Am J Epidemiol. 2005, 161: 412-422. 10.1093/aje/kwi063View ArticlePubMedGoogle Scholar
- Tang X, Liu D, Shishodia S, Ozburn N, Behrens C, Lee JJ, Hong WK, Aggarwal BB, Wistuba II: Nuclear factor-kappaB (NF-kappaB) is frequently expressed in lung cancer and preneoplastic lesions. Cancer. 2006, 107: 2637-2646. 10.1002/cncr.22315View ArticlePubMedGoogle Scholar
- Luo JL, Maeda S, Hsu LC, Yagita H, Karin M: Inhibition of NF-kappaB in cancer cells converts inflammation- induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression. Cancer Cell. 2004, 6: 297-305. 10.1016/j.ccr.2004.08.012View ArticlePubMedGoogle Scholar
- Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E, Ben Neriah Y: NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature. 2004, 431: 461-466. 10.1038/nature02924View ArticlePubMedGoogle Scholar
- Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, Kagnoff MF, Karin M: IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 2004, 118: 285-296. 10.1016/j.cell.2004.07.013View ArticlePubMedGoogle Scholar
- 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.0705316104PubMed CentralView ArticlePubMedGoogle Scholar
- Meylan E, Dooley AL, Feldser DM, Shen L, Turk E, Ouyang C, Jacks T: Requirement for NF-kappaB signalling in a mouse model of lung adenocarcinoma. Nature. 2009, 462: 104-107. 10.1038/nature08462PubMed CentralView ArticlePubMedGoogle Scholar
- Moghaddam SJ, Barta P, Mirabolfathinejad SG, Ammar-Aouchiche Z, Garza NT, Vo TT, Newman RA, Aggarwal BB, Evans CM, Tuvim MJ: Curcumin inhibits COPD-like airway inflammation and lung cancer progression in mice. Carcinogenesis. 2009, 30: 1949-1956. 10.1093/carcin/bgp229PubMed CentralView ArticlePubMedGoogle Scholar
- Chen Y, Thai P, Zhao YH, Ho YS, DeSouza MM, Wu R: Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop. J Biol Chem. 2003, 278: 17036-17043. 10.1074/jbc.M210429200View ArticlePubMedGoogle Scholar
- Molet S, Hamid Q, Davoine F, Nutku E, Taha R, Page N, Olivenstein R, Elias J, Chakir J: IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. J Allergy Clin Immunol. 2001, 108: 430-438. 10.1067/mai.2001.117929View ArticlePubMedGoogle Scholar
- 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.194.4.519PubMed CentralView ArticlePubMedGoogle Scholar
- Curtis JL, Freeman CM, Hogg JC: The immunopathogenesis of chronic obstructive pulmonary disease: insights from recent research. Proc Am Thorac Soc. 2007, 4: 512-521. 10.1513/pats.200701-002FMPubMed CentralView ArticlePubMedGoogle Scholar
- 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.xPubMed CentralView ArticlePubMedGoogle Scholar
- Bellocq A, Antoine M, Flahault A, Philippe C, Crestani B, Bernaudin JF, Mayaud C, Milleron B, Baud L, Cadranel J: Neutrophil alveolitis in bronchioloalveolar carcinoma: induction by tumor-derived interleukin-8 and relation to clinical outcome. Am J Pathol. 1998, 152: 83-92.PubMed CentralPubMedGoogle Scholar
- Redente EF, Orlicky DJ, Bouchard RJ, Malkinson AM: Tumor signaling to the bone marrow changes the phenotype of monocytes and pulmonary macrophages during urethane-induced primary lung tumorigenesis in A/J mice. Am J Pathol. 2007, 170: 693-708. 10.2353/ajpath.2007.060566PubMed CentralView ArticlePubMedGoogle Scholar
- Houghton AM, Rzymkiewicz DM, Ji H, Gregory AD, Egea EE, Metz HE, Stolz DB, Land SR, Marconcini LA, Kliment CR: Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Nat Med. 2010, 16: 219-223. 10.1038/nm.2084PubMed CentralView ArticlePubMedGoogle Scholar
- 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-03-3376View ArticlePubMedGoogle Scholar
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