Chromosome Instability Drives Metal-Induced Lung Cancer

项目概要/摘要 肺癌是癌症死亡的主要原因，几十年来生存率几乎没有改善。 对肺癌的理解和支持一直受到这种疾病仅仅是一种 事实上，其他因素也是导致这种疾病的主要因素。很多人肺 癌症患者从未使用过烟草，只有少数烟草使用者实际上会患肺癌。虽然 肺癌比结肠癌、乳腺癌和前列腺癌的死亡人数总和还要多，但它得到的联邦资助却更少 比单独的这些癌症都要多染色体不稳定性（CIN）是肺癌的标志。所有既定 肺致癌物导致CIN，但其机制却很少受到关注。金属暴露 是一个全球性的健康问题。金属会导致肺癌，致癌金属是烟草中的一种成分。 金属是不良的诱变剂，但可诱发CIN，然而，金属如何导致肺癌和CIN是不良的 明白我们的R35计划重点是了解金属致癌物如何诱导 肺癌的CIN。我们使用六价铬[Cr（VI）]，一种主要的公共卫生人类肺癌致癌物 尽管我们将比较Cr（VI）与其他金属肺的结局， 致癌物质。我们将研究Cr（VI）如何诱导结构和数值CIN，考虑人肺成纤维细胞， 上皮和诱导多能干细胞模型。我们将从单个细胞类型的研究进展到 更复杂的三维混合细胞培养研究。我们加强和加深对以下方面的了解： 这些机制与一个环境健康的方法，利用野生动物的能力，以抵抗 Cr（VI）诱导的CIN，并提供新的见解，其致癌机制。此外，我们最大限度地 这些发现的影响，通过将我们的结果转化为动物，并转化为一个强大的和独特的收集， 人类受试者和人群，从主要接触Cr（VI）的工人到混合接触Cr（VI）的工人， 金属暴露，包括Cr。这种结合人类、动物和细胞系的方法， 健康工具将使我们前所未有地深入了解金属如何诱导结构和数值CIN。特别是， 我们将定义：1）金属诱导的CIN的关键机制; 2）这些机制如何持续存在，并在 细胞水平导致肿瘤疾病; 3）它们如何转化为动物和人类。所以我们 拟议的R35计划将彻底改变我们对Cr（VI）、CIN、金属致癌作用和肺部的理解 同时也为涉及CIN的其他癌症提供了重要的见解。成果将包括： 在理解方面的科学突破：1）金属如何导致正常人类肺细胞成为肿瘤; 2)如何在肿瘤发生时检测到这种肿瘤转化; 3）如何更有效地靶向肺细胞， 4）如何预防肿瘤变化的发生，从而改善风险评估， 治疗和健康结果。

PROJECT SUMMARY/ABSTRACT Lung cancer is the leading cause of cancer death with little improvement in survivability over many decades. Understanding and support for lung cancer have suffered from the stigma that the disease is merely a consequence of tobacco use, when in fact other agents are a major factor in the disease. Many people with lung cancer have never used tobacco and only a minority of tobacco users actually get lung cancer. However, while lung cancer kills more people than colon, breast and prostate cancer combined, it receives less federal funding than each of these cancers alone. Chromosome instability (CIN) is a hallmark of lung cancer. All established lung carcinogens cause CIN, yet the mechanisms for how they do have received little attention. Metal exposure is a worldwide health concern. Metals cause lung cancer, and carcinogenic metals are a component in tobacco. Metals are poor mutagens but potently induce CIN, yet, how metals cause lung cancer and CIN is poorly understood. We focus our R35 program on understanding the mechanisms for how metal carcinogens induce CIN in lung cancer. We use hexavalent chromium [Cr(VI)], a human lung carcinogen of major public health concern, as our primary metal of interest, although we will compare Cr(VI) outcomes with other metal lung carcinogens. We will study how Cr(VI) induces structural and numerical CIN, considering human lung fibroblast, epithelial and induced pluripotent stem cell models. We will progress our studies from individual cell types to more complex, three-dimensional, mixed cell culture studies. We enhance and deepen our understanding of these mechanisms with a One Environmental Health approach, which leverages the ability of wildlife to resist Cr(VI)-induced CIN and provide novel insights into its carcinogenic mechanism. Moreover, we maximize the impact of these findings by translating our outcomes into animals and into a powerful and unique collection of human subjects and populations ranging from workers with primarily Cr(VI) exposure, to workers with a mixed metal exposure including Cr. This combined approach of humans, animals and cell lines with One Environmental Health tools will give us unprecedented insight into how metals induce structural and numerical CIN. In particular, we will define: 1) key mechanisms for metal-induced CIN; 2) how these mechanisms persist and are heritable at the cellular level to cause neoplastic disease; and 3) how they translate to animals and humans. Thus, our proposed R35 program will revolutionize our understanding of Cr(VI), CIN, metal carcinogenesis, and lung cancer while also providing important insights for other cancers that involve CIN. Outcomes will include major scientific breakthroughs in understanding: 1) how metals cause normal human lung cells to become neoplastic; 2) how to detect this neoplastic transformation when it occurs; 3) how to more effectively target lung cells that have transformed and 4) how to prevent neoplastic change from occurring, leading to improved risk assessment, treatments, and health outcomes for people exposed to metals.