Asbestos, Lung Cancers, and Mesotheliomas From Molecular Approaches to Targeting Tumor Survival Pathways
Asbestos, Lung Cancers, and Mesotheliomas From Molecular Approaches to Targeting Tumor Survival Pathways
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DOI：
10.1165/rcmb.2009-0206tr
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发表时间：
2010-02-01
影响因子：
6.4
通讯作者：
Mossman, Brooke T.
中科院分区：
文献类型：
--
作者：
Heintz, Nicholas H.;Janssen-Heininger, Yvonne M. W.;Mossman, Brooke T.
自我们在AJRCMB上发表研究结果以来，已经过去了15年，该研究结果表明，啮齿动物气管和间皮细胞中早期反应fos/jun原癌基因的诱导与石棉的纤维几何形状和致病性相关。我们的研究首次表明，青石棉和毛沸石（一种与土耳其地区恶性间皮瘤（Mesotheliomas）发展相关的纤维沸石矿物质）对信号应答的异常诱导导致基因表达改变。新的数据质疑当时广泛持有的观点，即石棉在肺癌和MM发展中的致癌作用是由于遗传毒性或致突变作用。我们小组后来的研究表明，石棉激活的原癌基因表达和几种信号通路是氧化还原依赖性的，这解释了为什么抗氧化剂和抗氧化酶在暴露于石棉后在肺和胸膜中升高，以及它们如何减轻石棉在体外或吸入后的许多表型和功能效应。由于这些原始的研究，我们的努力已经扩大到了解石棉诱导的氧化还原依赖的信号转导级联之间的接口，这些途径和细胞命运之间的关系，石棉和细胞的相互作用在石棉相关疾病的发展中的作用。相当重要的是，石棉激活的信号转导途径在肺癌和肺癌的生存和耐药性中也很重要。了解石棉纤维的致病特征和信号通路的失调，可以制定预防和治疗石棉相关疾病的策略。
Fifteen years have passed since we published findings in the AJRCMB demonstrating that induction of early response fos/jun proto-oncogenes in rodent tracheal and mesothelial cells correlates with fibrous geometry and pathogenicity of asbestos. Our study was the first to suggest that the aberrant induction of signaling responses by crocidolite asbestos and erionite, a fibrous zeolite mineral associated with the development of malignant mesotheliomas (MMs) in areas of Turkey, led to altered gene expression. New data questioned the widely held belief at that time that the carcinogenic effects of asbestos in the development of lung cancer and MM were due to genotoxic or mutagenic effects. Later studies by our group revealed that proto-oncogene expression and several of the signaling pathways activated by asbestos were redox dependent, explaining why antioxidants and antioxidant enzymes were elevated in lung and pleura after exposure to asbestos and how they alleviated many of the phenotypic and functional effects of asbestos in vitro or after inhalation. Since these original studies, our efforts have expanded to understand the interface between asbestos-induced redox-dependent signal transduction cascades, the relationship between these pathways and cell fate, and the role of asbestos and cell interactions in development of asbestos-associated diseases. Of considerable significance is the fact that the signal transduction pathways activated by asbestos are also important in survival and chemoresistance of MMs and lung cancers. An understanding of the pathogenic features of asbestos fibers and dysregulation of signaling pathways allows strategies for the prevention and therapy of asbestos-related diseases.