A/J Mouse As A Model For Lung Tumorigenesis Caused By Tobacco Smoke: Strengths And Weaknesses

Witschi, Hanspeter

doi:10.1080/01902140490494959

Cited by 65 publications

(68 citation statements)

References 54 publications

(59 reference statements)

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“…Although there is convincing evidence that carcinogens contained within cigarette smoke induce lung tumorigenesis (2)(3)(4)(5), additional mechanisms may contribute to the increased cancer risk in smokers.…”

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confidence: 99%

Cigarette Smoke Impairs NK Cell-Dependent Tumor Immune Surveillance

Лу¹,

Zavitz²,

Chen³

et al. 2007

The Journal of Immunology

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In this study, we investigated the impact of cigarette smoke on tumor immune surveillance and its consequences to lung tumor burden in a murine lung metastasis model. Cigarette smoke exposure significantly increased the numbers of lung metastases following B16-MO5 melanoma challenge. This effect was reversible; we observed significantly fewer tumor nodules following smoking cessation. Using RAG2−/− and RAG2−/−γc−/− mice, we provide strong evidence that increased tumor incidence was NK cell dependent. Furthermore, we show that cigarette smoke suppressed NK activation and attenuated NK CTL activity, without apparent effect on activating or inhibitory receptor expression. Finally, activation of NK cells through bone marrow-derived dendritic cells conferred protection against lung metastases in smoke-exposed mice; however, protection was not as efficacious as in sham-exposed mice. To our knowledge, this is the first experimental evidence showing that cigarette smoke impairs NK cell-dependent tumor immune surveillance and that altered immunity is associated with increased tumor burden. Our findings suggest that altered innate immunity may contribute to the increased risk of cancer in smokers.

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confidence: 99%

Cigarette Smoke Impairs NK Cell-Dependent Tumor Immune Surveillance

Лу¹,

Zavitz²,

Chen³

et al. 2007

The Journal of Immunology

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“…Most potent carcinogens are the cigarette smoke carcinogens, such as polycyclic aromatic hydrocarbons, tobacco-specific nitrosamine and benzo [a]pyrene (B[a]P) [3]. However, cigarette smoke itself is sufficient to induce reproducibly lung tumours in A/J mice after a 5-month exposure period followed by a crucial 4-month recovery period [4]. Exposure of B6C3F1 female mice to life-time (30 months) cigarette smoke resulted in 48% benign and malignant lung tumours through distinct (epi)genetic pathways [5].…”

Section: First Mouse Models For Lung Cancermentioning

confidence: 99%

Progress and applications of mouse models for human lung cancer

Seranno¹,

Meuwissen²

2010

Eur Respir J

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The continued progress of modelling lung cancer in mice has led not only to new means of understanding the molecular pathways governing human lung cancer, but it has also created a vast reservoir of alternative tools to test treatments against this malignancy. More sophisticated somatic mouse models for nonsmall cell lung cancer, small cell lung cancer and pulmonary squamous cell carcinoma have been generated that closely mimic human lung cancer. These models enable us to identify the cells of origin and the role of stem cells in the maintenance of the various types of lung cancer. Moreover, results of lung cancer intervention studies are now starting to reveal the full potential of these somatic mouse models as powerful pre-clinical models.KEYWORDS: Lung cancer, mouse models, nonsmall cell lung cancer, small cell lung cancer P rogress in whole genome approaches to detect genetic alterations in human lung cancer has resulted in the identification of a growing number of lung cancer-related genes. Genome-wide association studies, whether they are based on single-nucleotide polymorphism array studies or detecting changes in gene copy numbers via comparative genomic hybridisation arrays, link the occurrence and frequency of mutations in lung cancer-related genes to the well-defined phenotype of high numbers of human lung cancer. These lung cancer-related genes provide great potential as therapeutic targets for lung cancer intervention. Target validation then occurs through in vitro intervention studies of these specific genetic mutations and their respective molecular pathways in human lung cancer cell lines. However, in vitro cell culture studies are limited and cannot fully mimic the more complex in vivo onset of tumorigenesis and response to tumour therapy. Developing lung cancer in mouse models that harbour specific mutations will undoubtedly provide a further and better insight into the mutation-specific effects on lung tumour biology. Moreover, a high degree of pathophysological similarity between lung tumours from mouse models and their human counterparts will make it possible to use these mouse models for pre-clinical tests. Various intervention strategies against specific mutations can then be tested based on better evaluation of both specificity and efficacy in mouse lung tumours of every developing stage. Continuous innovation of techniques to manipulate the mouse genome has enabled us to adjust compound mouse models of lung cancer in such a way that they start to reproduce the more complex human lung cancer in a higher degree. Complementary to this, the number of genetically engineered mouse models for lung cancer is ever expanding. FIRST MOUSE MODELS FOR LUNG CANCER

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“…With the single exception of the A/J mouse strain [61,62], chronic exposure to cigarette smoke failed to increase the incidence of malignant tumours in the respiratory tract in mice, rats, hamsters, dogs and nonhuman primates as reviewed by COGGINS [63,64]. Despite considerable variation in the specific pulmonary responses to acute or chronic cigarette smoke exposure [7,8,65,66], there is no doubt that cigarette smoke adversely affects the lungs of laboratory animals in various ways, including the induction of airway wall inflammation and epithelial cell alterations, like goblet cell metaplasia.…”

Section: Inhalation Models Of Emphysemamentioning

confidence: 99%

Animal models of pulmonary emphysema: a stereologist's perspective

Fehrenbach¹

2006

Eur Respir Rev

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A variety of animal models have been suggested as models of pulmonary emphysema; these are critically discussed in the present article from a stereologist's perspective. In addition, a stereological design for the quantification of experimentally induced emphysema is proposed.On the basis of the widely accepted definition of pulmonary emphysema being an ''abnormal permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their walls,'' quantitative morphology is the only method with which to reliably assess the presence of emphysema. Recognising this, careful inspection of animal models that are based on instillation of elastase, genetic alterations, inhalation of cigarette smoke or induction of apoptosis, reveals that both criteria of emphysema definition were demonstrated in surprisingly few of them.Several aspects are suggested to be critical for the understanding of animal models of human emphysema. For example, genetic models that rely on the inhibition of the formation of alveoli during post-natal alveolarisation should clearly be distinguished from models that rely on the loss of mature alveoli after alveolarisation is complete. Furthermore, inhalation models that are characterised by exposed animals exhibiting a severe loss of body weight should carefully examine the relative contribution of intervention and weight loss, respectively. Models that rely on the exposure of juvenile animals for several weeks or even months should take into account the effects of normal lung growth and ageing.Stereology offers appropriate tools with which to quantify the parameters relevant to assess development and the regeneration of emphysema. Stereologists continue to develop tools that will help ascertain the reliability of established and new models. If inappropriate parameters continue to be used for the evaluation of animal models of emphysema, thinking and resources are likely to be misdirected and the models may limit rather than expand the understanding of human emphysema and the development of new therapies.

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A/J Mouse As A Model For Lung Tumorigenesis Caused By Tobacco Smoke: Strengths And Weaknesses

Cited by 65 publications

References 54 publications

Cigarette Smoke Impairs NK Cell-Dependent Tumor Immune Surveillance

Cigarette Smoke Impairs NK Cell-Dependent Tumor Immune Surveillance

Progress and applications of mouse models for human lung cancer

Animal models of pulmonary emphysema: a stereologist's perspective

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