Chromosome Instability Drives Metal-Induced Lung Cancer

受资助家长助学金项目摘要 肺癌是癌症死亡的主要原因，几十年来存活率几乎没有改善。 对肺癌的理解和支持受到了耻辱，即这种疾病只是一种 烟草使用的后果，而事实上其他因素是导致这种疾病的主要因素。很多人都有肺病 癌症患者从未使用过烟草，只有一小部分吸烟者真正患上了肺癌。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要多，它得到的联邦资金更少 而不是这些癌症中的每一种。染色体不稳定(CIN)是肺癌的一个标志。都已建立 肺癌致癌物质会引起CIN，但它们的致癌机制却鲜有人关注。金属暴露量 是一个世界性的健康问题。金属会导致肺癌，而致癌金属是烟草中的一种成分。 金属是很差的诱变剂，但却能有效地诱发CIN，然而，金属是如何导致肺癌和CIN的还不是很清楚 明白了。我们的R35计划的重点是了解金属致癌物如何诱发的机制 肺癌中CIN的表达。我们使用六价铬[Cr(VI)]，这是一种对人类主要公共健康具有致癌作用的人类肺癌物质 关注，作为我们感兴趣的主要金属，尽管我们将比较铬(VI)的结果与其他金属肺 致癌物质。我们将研究铬(VI)是如何诱导结构和数量上的CIN的，考虑到人肺成纤维细胞， 上皮性和诱导性多能干细胞模型。我们的研究将从单个细胞类型发展到 更复杂、立体、混合的细胞培养研究。我们增进和加深了对 这些机制以一种环境健康的方法，利用野生动物的抵抗能力 并对其致癌机制提供了新的见解。此外，我们将最大化 通过将我们的结果转化为动物，并转化为强大而独特的 人类受试者和人群，从主要接触铬(VI)的工人到混合接触铬(VI)的工人 金属暴露，包括铬。人、动物、细胞系在一个环境中的结合方法 健康工具将为我们提供前所未有的洞察力，让我们了解金属是如何导致结构性和数值CIN的。特别是， 我们将定义：1)金属诱导的CIN的关键机制；2)这些机制如何持续和可遗传 导致肿瘤疾病的细胞水平；以及3)它们如何传递给动物和人类。因此，我们的 建议的R35计划将彻底改变我们对铬(VI)、CIN、金属致癌和肺的理解 同时也为涉及宫颈上皮内瘤变的其他癌症提供了重要见解。结果将包括主要 在理解方面的科学突破：1)金属如何导致正常的人类肺细胞发生肿瘤； 2)如何在发生时检测到这种肿瘤性转化；3)如何更有效地靶向 以及4)如何防止肿瘤变化的发生，从而改进风险评估， 暴露于金属的人的治疗和健康结果。

PROJECT SUMMARY OF THE FUNDED PARENT GRANT 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.