Lung cancer is the leading cause of cancer-related mortality in both men and women throughout the world. This disease is strongly associated with tobacco smoking. The aim of this manuscript was to establish an in vitro model that mimics the chronic exposures of alveolar epithelial type II cells to the tobacco-specific nitrosamine carcinogen, NNK. Immortalized non-neoplastic alveolar epithelial cells type II, (E10 cells), from BALB/c mice were exposed to low concentration of NNK (100 pM) during 5, 10, 15, and 20 cycles of 48 h. NNK-transformed cells showed an increase of proliferation rate and motility. Moreover, these cells underwent epithelial-to-mesenchymal transition (EMT). Increased migratory capacity and EMT were correlated to the time of exposure to NNK. NNK-transformed cells were tested for their growth and metastatic capacity in vivo. Subcutaneous injection of cells exposed to NNK for 20 cycles (E10-NNK20 clone) into BALB/c mice led to the formation of subcutaneous tumors that arose after 40 ± 17 d in all animals, which died 95 ± 18 d after cell inoculation, with lymph nodes and lung metastasis. The morphological characteristics of tumors were compatible with metastatic undifferentiated carcinoma. Cells exposed to NNK for 5-10 cycles did not display metastatic capacity, while those exposed for 15 cycles displayed low capacity. Our results show that prolonged exposures to NNK led the cells to increasingly acquire malignant properties. The cellular model presented in this study is suitable for studying the molecular events involved in the different stages of malignant transformation.

译文

:肺癌是全世界男女癌症相关死亡率的主要原因。这种疾病与吸烟密切相关。该手稿的目的是建立一个体外模型,该模型模仿肺泡II型肺泡上皮细胞长期暴露于烟草特有的亚硝胺致癌物NNK。来自BALB / c小鼠的永生化II型非肿瘤性肺泡上皮细胞(E10细胞)在48?h的5、10、15和20个周期中暴露于低浓度的NNK(100 pM)。 NNK转化的细胞显示出增殖速率和运动性的增加。而且,这些细胞经历了上皮到间充质转化(EMT)。迁徙能力和EMT的增加与接触NNK的时间有关。测试了NNK转化的细胞的体内生长和转移能力。在BALB / c小鼠中皮下注射暴露于NNK 20个周期的细胞(E10-NNK20克隆)导致皮下肿瘤的形成,所有动物在40±±17 d后出现,在接种细胞后95±±18 d死亡。淋巴结转移和肺转移。肿瘤的形态学特征与转移性未分化癌相容。暴露于NNK 5-10个周期的细胞不显示转移能力,而暴露15个周期的细胞则显示低转移能力。我们的结果表明,长时间暴露于NNK会使细胞越来越多地获得恶性特性。在这项研究中提出的细胞模型适用于研究与恶性转化的不同阶段有关的分子事件。

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