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。 人们对肺癌的理解和支持都受到了这种疾病仅仅是一种耻辱的困扰。 烟草使用的后果，而事实上其他因素是该疾病的主要因素。很多肺病患者 癌症从未使用过烟草，只有少数吸烟者真正患上肺癌。然而，虽然 肺癌导致的死亡人数比结肠癌、乳腺癌和前列腺癌的总和还多，但获得的联邦资助较少 比单独的这些癌症中的每一种都重要。染色体不稳定（CIN）是肺癌的一个标志。全部成立 肺癌致癌物会导致 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。 金属是弱诱变剂，但能有效诱发 CIN，但金属如何导致肺癌和 CIN 的研究还很有限 明白了。我们的 R35 计划的重点是了解金属致癌物的诱发机制 肺癌中的 CIN。我们使用六价铬 [Cr(VI)]，这是一种对公共健康具有重大影响的人类肺癌致癌物 关注，作为我们感兴趣的主要金属，尽管我们将比较 Cr(VI) 的结果与其他金属肺 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。我们将把我们的研究从单个细胞类型发展到 更复杂的三维混合细胞培养研究。我们增强并加深了对 这些机制采用“单一环境健康”方法，利用野生动物的抵抗能力 Cr(VI) 诱导的 CIN 并为其致癌机制提供了新的见解。此外，我们最大化 通过将我们的成果转化为动物并转化为强大而独特的集合来发挥这些发现的影响 人类受试者和人群范围从主要接触 Cr(VI) 的工人到混合接触 Cr(VI) 的工人 金属暴露，包括铬。这种将人类、动物和细胞系与 One Environmental 相结合的方法 健康工具将为我们提供前所未有的洞察力，让我们了解金属如何诱发结构性和数值性 CIN。特别是， 我们将定义：1）金属诱发CIN的关键机制； 2）这些机制如何持续存在并可遗传 细胞水平引起肿瘤疾病； 3）它们如何转化为动物和人类。因此，我们的 拟议的 R35 计划将彻底改变我们对 Cr(VI)、CIN、金属致癌和肺癌的理解 癌症，同时也为涉及 CIN 的其他癌症提供重要见解。成果将包括主要 认识上的科学突破：1）金属如何导致正常人类肺细胞发生肿瘤； 2）如何在肿瘤转化发生时检测到它； 3）如何更有效地靶向肺细胞 已经转变，4）如何预防肿瘤变化的发生，从而改进风险评估， 接触金属的人的治疗和健康结果。

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.