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: 8846114
• 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 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8846114
• 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; Route; Safety; Signal Pathway; Signal Transduction; Specimen; Testing; Time; Tumor-Derived; Work; Xenograft Model; base; cancer risk; cancer stem cell; carcinogenesis; carcinogenicity; cell transformation; design; disorder prevention; driving force; epithelial to mesenchymal transition; expectation; exposed human population; in vivo; innovation; lung carcinogenesis; nanomaterials; nanoscience; novel; pre-clinical; response; screening; 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）：纳米技术作为下一个工业革命具有巨大的希望，并有望成为美国经济复苏和发展的主要驱动力。该项目的长期目标是通过理解生化机制和物理化学因素来实现安全的纳米技术，从而影响纳米材料暴露的不良健康影响。该建议专门解决了慢性肺暴露后碳纳米管（CNT）的致癌作用。肺癌是癌症死亡的主要原因，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，CNT可以诱导肿瘤和肿瘤相关的病理，但是尚不清楚的基本机制和关键因素尚不清楚，这限制了人类风险评估和预防疾病。我们假设人类肺上皮细胞长期暴露于CNT中，通过涉及p53失调和诱导癌症干细胞（CSC）和上皮间质转换（EMT）的复杂机制诱导恶性转化和致癌作用。我们还提出，表征这些生物学变化的结合生物标志物可以预测CNT诱导的致癌作用。提出了三个具体目标。在AIM 1中，我们将测试CNT癌变中p53失调的需求，并确定控制CNT致癌性的关键理化特性。 AIM 2将研究CSC在CNT癌变中的作用，并确定CNT致癌反应的独特CSC标记。 AIM 3将表征EMT网络并确定其在CSC采集和CNT癌变中的作用。我们将确定结合生物标志物来预测CNT癌变并验证其在肺部原位异种移植模型中的临床使用。我们的期望是，在 该项目的结论是，我们将确定CNT癌变的生物标志物，并确定确定CNT致癌性的关键理化因素。这项工作很重要，因为它将对CNT癌变的风险评估和预防安全纳米技术产生总体影响。我们预计影响会很大，因为该项目的发现非常适用于各种纳米材料。提出的工作具有创新性，因为它结合了CSC和EMT的新概念，以揭示CNT诱导的致癌作用的潜在机制，而目前尚不清楚。此外，该项目中开发的实验模型，例如慢性暴露和肺直系异种移植模型，可以用作目前缺乏且极其需要的纳米材料的致癌性测试的预测性筛选工具。