Chromosome Instability Drives Metal-Induced Lung Cancer

染色体不稳定性导致金属诱发肺癌

• 批准号: 10656428
• 负责人: John Pierce Wise
• 金额: $ 85.64万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2029-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656428
• 关键词: 3-Dimensional; Animals; Attention; Cancer Etiology; Carcinogens; Cell Line; Cells; Cessation of life; Chromosomal Instability; Collection; Colon Carcinoma; Complex; Disease; Environmental Health; Epithelium; Event; Fibroblasts; Funding; Health; Heritability; Human; Individual; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Metal Carcinogenesis; Metal exposure; Metals; Minority; Mutagens; Neoplastic Cell Transformation; Outcome; Persons; Population; Public Health; Risk Assessment; Tobacco; Tobacco use; Translating; United States; carcinogenicity; cell type; chromium hexavalent ion; human subject; improved; induced pluripotent stem cell; insight; interest; malignant breast neoplasm; mixed cell culture; neoplastic; novel; novel strategies; prevent; programs; social stigma; stem cell model; tobacco user; tool

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.

项目摘要/摘要 肺癌是癌症死亡的主要原因，几十年来，生存能力几乎没有提高。 对肺癌的理解和支持已经遭受了疾病仅仅是一种 烟草使用的结果，实际上其他药物是该疾病的主要因素。许多人患有肺 癌症从未使用过烟草，只有少数烟草使用者实际上患有肺癌。但是， 肺癌杀死的人数比结肠，乳腺癌和前列腺癌的人数多，联邦政府的资金较少 比仅这些癌症中的每一个。染色体不稳定性（CIN）是肺癌的标志。都建立了 肺致癌物引起CIN，但是它们如何受到关注的机制。金属暴露 是全球健康问题。金属引起肺癌，致癌金属是烟草中的一个组成部分。 金属是较差的诱变剂，但有力地诱导CIN，但是，金属如何引起肺癌，而CIN却很差 理解。我们将R35计划重点放在理解金属致癌物如何诱导的机制上 肺癌中的CIN。我们使用六价铬[CR（VI）]，这是主要公共卫生的人类肺癌 担心，作为我们主要感兴趣的金属，尽管我们将将CR（VI）结果与其他金属肺进行比较 致癌物。我们将研究CR（VI）如何诱导结构和数值CIN，考虑到人类肺成纤维细胞， 上皮和诱导多能干细胞模型。我们将研究我们的研究从单个细胞类型到 更复杂，三维的混合细胞培养研究。我们增强并加深了我们对 这些机制采用一种环境健康方法，利用野生动植物抵抗的能力 CR（VI）诱导的CIN并提供了有关其致癌机制的新见解。而且，我们最大化 这些发现的影响是通过将我们的结果转化为动物，并成为强大而独特的集合 人类受试者和人口，从主要是CR（VI）接触的工人到有混合的工人 金属暴露在内，包括Cr。人类，动物和细胞系的这种结合方法与一个环境 健康工具将使我们对金属如何诱导结构和数值CIN的洞察力。尤其， 我们将定义：1）金属诱导的CIN的关键机制； 2）这些机制如何持续并可以遗传 引起肿瘤疾病的细胞水平； 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，金属致癌和肺的理解 癌症同时还为其他涉及CIN的癌症提供重要见解。成果将包括专业 理解中的科学突破：1）金属如何导致正常的人肺细胞成为肿瘤； 2）如何在发生这种肿瘤转化时； 3）如何更有效地靶向肺部细胞 已经改变了4）如何防止肿瘤发生变化，从而改善了风险评估， 治疗和暴露于金属的人的健康成果。