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A. Muñoz

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    E09 - Chemoprevention (ID 9)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      E09.1 - Preclinical Models for Lung Cancer Prevention (ID 413)

      14:00 - 15:30  |  Author(s): A. Muñoz

      • Abstract
      • Presentation
      • Slides

      Lung cancer risk models and screening protocols are becoming more precise and, consequently, there is an increasing interest in developing new chemoprevention strategies for lung cancer. A number of compounds, among them several phytochemicals, have been proposed as potential lung cancer chemopreventive agents based on studies using rodent models. New preclinical studies involving novel chemopreventive compounds or more efficacious dosing strategies are required and their success will depend in part on the quality of the experimental models. In our presentation we will give an update of the available and newly emerging rodent models for the preclinical study of potential chemopreventive interventions for lung cancer. In order to fully recapitulate the complexities of human lung cancer, different animal models have been developed. These models can be divided into chemically-induced lung cancer and genetically engineered mouse models (GEMMs). Most chemoprevention studies have been performed on mouse models of lung adenocarcinoma (ADC) induced by a number of chemical carcinogens found in tobacco combustion products. The A/J mouse strain has been utilized primarily for these studies since these mice develop lung tumors rapidly after treatment with certain carcinogens such as anthracene, urethane, nicotine-derived nitrosamine ketone (NNK), other nitrosamines, benzo(a)pyrene (BaP), or vinyl carbamate. There are several well established chemically induced mouse ADC models which have been most frequently used in the assessment of the preventive potential of various types of agents: Genetic differences between ADC and squamous cell carcinoma (SCC) are also paralleled in the development of animal models. Skin painting with nitroso-tris-chloroethylurea (NTCU) is the best established protocol to produce lung SCC in susceptible mice and it has already been used for chemoprevention studies. In our lab, we have studied some phenotypic and genetic traits of the NTCU induced SCC, and we have used this model to analyse SCC-specific drug efficacy. GEMMs of lung cancer, mainly leading to adenomas or ADCs have also been used in chemopreventive preclinical studies. A plethora of GEMMs for lung carcinogenesis are available with single or combined genetic alterations in oncogenes or tumor suppressors. Several mouse models of lung cancer have been developed with mutation of Kras as the initiating oncogenic event. In the Kras[LSLG12D/+ ]knock-in mouse model, expression of oncogenic Kras is achieved by intratracheal inoculation with adenoviruses carrying Cre-recombinase The Kras[LSLG12D/+ ]model represents a highly relevant GEMM as it recapitulates many aspects of human ADC oncogenesis, including the full spectrum of lesions from early atypical adenomatous hyperplasia (AAH) to adenocarcinoma, and expresses human NSCLC gene signatures. Interestingly, combined mutant KRAS expression with additional genetic alterations such as p53, PTEN or LKB1 loss results in advanced stages of lung cancer including metastasis. To date, there is only one GEMM leading to pure squamous histology with many human SCC traits, recently developed in kinase-dead IKKα knock-in mice. Some years ago a mouse model for SCLC was developed by conditional inactivation of Rb1 and Trp53 in mouse lung epithelial cells. A newly developed model of SCLC incorporates p130 knockout and accelerates the formation of SCLC. Finally, mouse models for inflammation-driven lung carcinogenesis are helping to understand the role of smoking induced inflammation in lung cancer. We recently found that silica-induced chronic lung inflammation markedly increases the incidence and multiplicity of mouse lung adenomas and ADCs following N-nitrosodimethylamine (NDMA) treatment. These results are in concordance with other animal models that explore the effects of different inflammatory agents in chemically-induced lung tumor promotion. One of the key practical points regarding the relevance of these animal models in developing new chemoprevention strategies is the extent to which they recapitulate human lung cancer multistep progression at the cellular and molecular levels.. The pathological and molecular likes and dislikes between human lung cancer and the most frequently used animal models will be discussed during the presentation. The quantitative assessment of tumor volume progression in cancers affecting internal organs such the lung is more difficult than the assessment of lesions that are superficial (for example, breast or skin). New imaging technologies such as respiratory-gated micro-CT scans for small animals allow performing longitudinal studies on animal models of lung cancer. Micro-CT has been mainly used to monitor tumor growth and to assess the response or the resistance to therapeutic drugs. The potential of micro-CT imaging in lung cancer chemoprevention studies has been already highlighted. Standardization of protocols, improved resolution, more robust and faster image acquisition and, fully automatic and properly validated quantification algorithms need to be implemented before micro-CT imaging can show its full potential in the assessment of chemoprevention therapies.

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