Susceptibility to neoplastic and non-neoplastic pulmonary diseases in mice: Genetic similarities

Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
AJP Lung Cellular and Molecular Physiology (Impact Factor: 4.08). 11/2004; 287(4):L685-703. DOI: 10.1152/ajplung.00223.2003
Source: PubMed


Chronic inflammation predisposes toward many types of cancer. Chronic bronchitis and asthma, for example, heighten the risk of lung cancer. Exactly which inflammatory mediators (e.g., oxidant species and growth factors) and lung wound repair processes (e.g., proangiogenic factors) enhance pulmonary neoplastic development is not clear. One approach to uncover the most relevant biochemical and physiological pathways is to identify genes underlying susceptibilities to inflammation and to cancer development at the same anatomic site. Mice develop lung adenocarcinomas similar in histology, molecular characteristics, and histogenesis to this most common human lung cancer subtype. Over two dozen loci, called Pas or pulmonary adenoma susceptibility, Par or pulmonary adenoma resistance, and Sluc or susceptibility to lung cancer genes, regulate differential lung tumor susceptibility among inbred mouse strains as assigned by QTL (quantitative trait locus) mapping. Chromosomal sites that determine responsiveness to proinflammatory pneumotoxicants such as ozone (O3), particulates, and hyperoxia have also been mapped in mice. For example, susceptibility QTLs have been identified on chromosomes 17 and 11 for O3-induced inflammation (Inf1, Inf2), O3-induced acute lung injury (Aliq3, Aliq1), and sulfate-associated particulates. Sites within the human and mouse genomes for asthma and COPD phenotypes have also been delineated. It is of great interest that several susceptibility loci for mouse lung neoplasia also contain susceptibility genes for toxicant-induced lung injury and inflammation and are homologous to several human asthma loci. These QTLs are described herein, candidate genes are suggested within these sites, and experimental evidence that inflammation enhances lung tumor development is provided.

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    • "Some of the mechanisms involved in pulmonary diseases, such as idiopathic pulmonary fibrosis (IPF) and cancer, include activation of mitogenic signal transduction pathways, dyregulation of GJIC [21], and induction of inflammation pathways [1]–[3], [22]–[24], which likely interact to elicit the observed effects (eg. promotion of initiated cells during carcinogenesis). "
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    ABSTRACT: Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental and occupational toxicants, which are a major human health concern in the U.S. and abroad. Previous research has focused on the genotoxic events caused by high molecular weight PAHs, but not on non-genotoxic events elicited by low molecular weight PAHs. We used an isomeric pair of low molecular weight PAHs, namely 1-Methylanthracene (1-MeA) and 2-Methylanthracene (2-MeA), in which only 1-MeA possessed a bay-like region, and hypothesized that 1-MeA, but not 2-MeA, would affect non-genotoxic endpoints relevant to tumor promotion in murine C10 lung cells, a non-tumorigenic type II alveolar pneumocyte and progenitor cell type of lung adenocarcinoma. The non-genotoxic endpoints assessed were dysregulation of gap junction intercellular communication function and changes in the major pulmonary connexin protein, connexin 43, using fluorescent redistribution and immunoblots, activation of mitogen activated protein kinases (MAPK) using phosphospecific MAPK antibodies for immunoblots, and induction of inflammatory genes using quantitative RT-PCR. 2-MeA had no effect on any of the endpoints, but 1-MeA dysregulated gap junctional communication in a dose and time dependent manner, reduced connexin 43 protein expression, and altered membrane localization. 1-MeA also activated ERK1/2 and p38 MAP kinases. Inflammatory genes, such as cyclooxygenase 2, and chemokine ligand 2 (macrophage chemoattractant 2), were also upregulated in response to 1-MeA only. These results indicate a possible structure-activity relationship of these low molecular weight PAHs relevant to non-genotoxic endpoints of the promoting aspects of cancer. Therefore, our novel findings may improve the ability to predict outcomes for future studies with additional toxicants and mixtures, identify novel targets for biomarkers and chemotherapeutics, and have possible implications for future risk assessment for these PAHs.
    PLoS ONE 06/2013; 8(6):e65150. DOI:10.1371/journal.pone.0065150 · 3.23 Impact Factor
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    • "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 [30]. 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. "
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    ABSTRACT: 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.
    Molecular Cancer 01/2012; 11(1):4. DOI:10.1186/1476-4598-11-4 · 4.26 Impact Factor
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    • "MJs in the black bottles were given to mice for 12 hr (from 8:00 p.m. to 8:00 a.m.) At week 22, lung proliferative lesions were diagnosed as hyperplasia and tumors, and we did not subclassify the tumors into adenoma and adenocarcinoma, because of the difficulty in evaluating malignancy [39, 40]. Pulmonary tumors (adenoma or adenocarcinoma) were developed in all mice treated with NNK. "
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    ABSTRACT: β-Cryptoxanthin, a carotenoid, and hesperidin, a flavonoid, possess inhibitory effects on carcinogenesis in several tissues. We recently have prepared a pulp (CHRP) and citrus juices (MJ2 and MJ5) from a satsuma mandarin (Citrus unshiu Mar.) juice (MJ). They contain high amounts of β-cryptoxanthin and hesperidin. We have demonstrated that CHRP and/or MJs inhibit chemically induced rat colon, rat tongue, and mouse lung tumorigenesis. Gavage with CHRP resulted in an increase of activities of detoxifying enzymes in the liver, colon, and tongue rats'. CHRP and MJs were also able to suppress the expression of proinflammatory cytokines and inflammatory enzymes in the target tissues. This paper describes the findings of our in vivo preclinical experiments to develop a strategy for cancer chemoprevention of colon, tongue, and lung neoplasms by use of CHRP and MJs.
    BioMed Research International 01/2012; 2012(18):516981. DOI:10.1155/2012/516981 · 2.71 Impact Factor
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