Antagonistic growth regulation of cell lines derived from human lung adenocarcinomas of Clara cell and aveolar type II cell lineage: Implications for chemoprevention.
Antagonistic growth regulation of cell lines derived from human lung adenocarcinomas of Clara cell and aveolar type II cell lineage: Implications for chemoprevention.
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DOI：
10.3892/ijo.24.6.1467
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发表时间：
2004-06
影响因子：
5.2
通讯作者：
H. Adissu;H. Schuller
中科院分区：
文献类型：
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作者：
H. Adissu;H. Schuller
肺癌仍然是工业化国家癌症死亡的主要原因，并且迫切需要开发预防性治疗，其抑制戒烟的吸烟者中启动的细胞进展为明显的肺癌。小鼠肺腺癌模型被广泛用于测试潜在的癌症预防剂。这些肿瘤属于肺泡II型细胞谱系，表达生长调节信号转导途径，该途径受表皮生长因子和蛋白激酶C刺激，同时受增加细胞内环AMP（cAMP）的药物抑制。相比之下，在仓鼠中诱导的肺腺癌源自支气管和细支气管Clara细胞，处于β-肾上腺素能受体控制下，并且其发展由增加细胞内cAMP的试剂促进。任一细胞谱系的腺癌在人类中发展，提高了由于cAMP刺激而在鼠肺癌模型中具有强化学预防活性的药剂可能选择性地促进源自Clara细胞的人肺腺癌的可能性。因此，我们比较了β-肾上腺素能激动剂异丙肾上腺素和cAMP福司可林的激活剂在受控的体外条件下对表达Clara细胞表型的人肺腺癌细胞系NCI-H322与表达肺泡II型细胞特征的人肺腺癌细胞系A549的作用。我们的数据表明，异丙肾上腺素显着刺激NCI-H322细胞中的cAMP、ERK 1/2活性和DNA合成，并且这种反应涉及EGF受体的反式激活。与此相反，我们发现异丙肾上腺素对A549细胞没有影响，而毛喉素显着抑制DNA合成和ERK 1/2活性。我们的研究结果是一致的解释，人类肺腺癌的克拉拉细胞系是高度敏感的β-肾上腺素能激动剂和其他药物，刺激cAMP的癌症促进作用，而人类癌症的相同的组织学家族，但来自肺泡II型细胞是耐β-肾上腺素能激动剂，并响应减少细胞生长的cAMP的刺激。我们的研究结果表明，一些广泛宣传的癌症预防剂，如绿色茶，类维生素A和β-胡萝卜素是不安全的吸烟者或戒烟者使用，由于其肿瘤促进作用，通过刺激cAMP对克拉拉细胞系的启动细胞。
Lung cancer continues to be the leading cause of cancer death in industrialized countries and there is an urgent need for the development of preventive treatments that inhibit the progression of initiated cells into overt lung cancer in smokers who quit. Murine pulmonary adenocarcinoma models are widely used to test prospective cancer preventive agents. These tumors are of alveolar type II cell lineage, express growth-regulating signal transduction pathways that are stimulated by epidermal growth factor and protein kinase C while being inhibited by agents that increase intracellular cyclic AMP (cAMP). By contrast, pulmonary adenocarcinomas induced in hamsters are derived from bronchial and bronchiolar Clara cells, are under beta-adrenergic receptor control and their development is promoted by agents that increase intracellular cAMP. Adenocarcinomas of either cell lineage develop in humans, raising the possibility that agents with strong chemopreventive activity in murine lung cancer models due to stimulation of cAMP may selectively promote human pulmonary adenocarcinomas derived from Clara cells. We therefore compared the effects of the beta-adrenergic agonist isoproterenol and the activator of cAMP forskolin under controlled in vitro conditions on the human pulmonary adenocarcinoma cell line NCI-H322 which expresses a Clara cell phenotype versus the human pulmonary adenocarcinoma cell line A549 which expresses features of alveolar type II cells. Our data show that isoproterenol significantly stimulated cAMP, ERK1/2 activity and DNA synthesis in NCI-H322 cells and that this response involved transactivation of the EGF receptor. By contrast, we found that isoproterenol had no effect on A549 cells whereas forskolin significantly inhibited DNA synthesis and ERK1/2 activity. Our findings are consistent with the interpretation that human pulmonary adenocarcinomas of Clara cell lineage are highly sensitive to the cancer promoting effects of beta-adrenergic agonists and other agents that stimulate cAMP whereas human cancers of the same histological family but derived from alveolar type II cells are resistant to beta-adrenergic agonists and respond with a reduction in cell growth to stimulation of cAMP. Our findings suggest that some widely advertised cancer preventive agents such as green tea, retinoids and beta-carotenes are unsafe to be used by smokers or by ex-smokers due to their tumor promoting effects via stimulation of cAMP on initiated cells of Clara cell lineage.