Induction of Neoplastic Transformation and Cancer Stem Cells by Carbon Nanotubes

碳纳米管诱导肿瘤转化和癌症干细胞

• 批准号: 9024527
• 负责人: Yon Rojanasakul
• 金额: $ 33.53万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-06 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9024527
• 关键词: Acute; Address; Affect; Animal Model; Animals; Asbestos; Biochemical; Biological; Biological Markers; Biology; Cancer Etiology; Carbon Nanotubes; Carcinogenesis Mechanism; Carcinogenicity Tests; Cells; Cessation of life; Characteristics; Chronic; Complex; Data; Development; Developmental Process; Dose; Early Diagnosis; Economics; Environmental and Occupational Exposure; Epithelial; Epithelial Cells; Exhibits; Experimental Models; Exposure to; Fiber; Future; Genes; Genomics; Health; Human; Hyperplasia; Link; Lung; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Medicine; Mesenchymal; Metals; Methodology; Modeling; Mus; Nanotechnology; Neoplastic Cell Transformation; Pathology; Prevention; Prevention strategy; Process; Property; Protein p53; Recovery; Research; Risk; Risk Assessment; Risk Factors; Role; Safety; Signal Pathway; Signal Transduction; Specimen; TP53 gene; Testing; Time; Tumor-Derived; Work; Xenograft Model; base; biomarker development; cancer risk; cancer stem cell; carcinogenesis; carcinogenicity; cell transformation; design; disorder prevention; driving force; epithelial to mesenchymal transition; expectation; exposed human population; exposure route; in vivo; innovation; lung carcinogenesis; nanomaterials; nanoscience; novel; pre-clinical; response; screening; specific biomarkers; tool; tumor; tumor growth; tumor initiation; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Nanotechnology holds great promise as the next industrial revolution and is expect to be a major driving force for the U.S. economic recovery and development. The long-term objective of this project is to enable safe nanotechnology through the understanding of biochemical mechanisms and physicochemical factors influencing the adverse health effects of nanomaterial exposure. This proposal specifically addresses the carcinogenic effects of carbon nanotubes (CNT) following chronic pulmonary exposure. Lung cancer is the leading cause of cancer death, and environmental and occupational exposure is the major cause of most cases. Recent studies have shown that CNT can induce tumors and tumor-associated pathologies, but the underlying mechanisms and key contributing factors are unclear, which limits human risk assessment and disease prevention. We hypothesize that chronic exposure of human lung epithelial cells to CNT induces malignant transformation and carcinogenesis through complex mechanisms that involve p53 dysregulation and induction of cancer stem cells (CSC) and epithelial mesenchymal transition (EMT). We also propose that combination biomarkers that characterize these biological changes could be predictive of CNT-induced carcinogenesis. Three specific aims are proposed. In Aim 1, we will test the requirement of p53 dysregulation in CNT carcinogenesis and determine key physicochemical properties controlling CNT carcinogenicity. Aim 2 will study the role of CSC in CNT carcinogenesis and determine the unique CSC markers for CNT carcinogenic responses. Aim 3 will characterize the EMT network and determine its role in CSC acquisition and CNT carcinogenesis. We will identify combination biomarkers to predict CNT carcinogenesis and validate their pre- clinical use in lung orthotopic xenograft models. Our expectations are that, at the conclusion of this project, we will have determined the biomarkers for CNT carcinogenesis and identified key physicochemical factors determining the carcinogenicity of CNT. This work is important because of the overall impact it will have on risk assessment and prevention of CNT carcinogenesis and development of safe nanotechnology. We expect the impact to be broad since the findings from this project are highly applicable to various nanomaterials. The proposed work is innovative because it combines the novel concepts of CSC and EMT to unveil the underlying mechanisms of CNT-induced carcinogenesis which are largely unknown at present. In addition, the experimental models developed in this project, e.g. chronic exposure and lung orthotopic xenograft models, could be used as predictive screening tools for carcinogenicity testing of nanomaterials which are currently lacking and greatly needed.

描述（由申请人提供）：纳米技术作为下一次工业革命前景广阔，有望成为美国经济复苏和发展的主要推动力。该项目的长期目标是通过了解影响纳米材料暴露对健康产生不利影响的生化机制和物理化学因素，实现安全的纳米技术。该提案特别针对慢性肺部暴露后碳纳米管（CNT）的致癌作用。肺癌是癌症死亡的主要原因，而环境和职业暴露是大多数病例的主要原因。最近的研究表明，碳纳米管可以诱发肿瘤和肿瘤相关病理，但其潜在机制和关键影响因素尚不清楚，这限制了人类风险评估和疾病预防。我们假设人肺上皮细胞长期暴露于 CNT 会通过复杂的机制诱导恶性转化和癌变，这些机制涉及 p53 失调以及诱导癌症干细胞 (CSC) 和上皮间质转化 (EMT)。我们还提出，表征这些生物变化的组合生物标志物可以预测碳纳米管诱导的致癌作用。提出了三个具体目标。在目标 1 中，我们将测试 CNT 致癌过程中 p53 失调的要求，并确定控制 CNT 致癌性的关键理化特性。目标 2 将研究 CSC 在 CNT 致癌作用中的作用，并确定 CNT 致癌反应的独特 CSC 标记。目标 3 将描述 EMT 网络的特征，并确定其在 CSC 获取和 CNT 癌变中的作用。我们将确定组合生物标志物来预测 CNT 致癌作用并验证其在肺原位异种移植模型中的临床前用途。我们的期望是，在 在该项目结束时，我们将确定 CNT 致癌的生物标志物，并确定决定 CNT 致癌性的关键理化因素。这项工作很重要，因为它将对碳纳米管致癌的风险评估和预防以及安全纳米技术的发展产生总体影响。我们预计影响将是广泛的，因为该项目的研究结果非常适用于各种纳米材料。这项工作具有创新性，因为它结合了 CSC 和 EMT 的新概念，揭示了目前尚不清楚的 CNT 诱导致癌的潜在机制。此外，该项目开发的实验模型，例如慢性暴露和肺原位异种移植模型可用作目前缺乏且急需的纳米材料致癌性测试的预测筛选工具。