Induction of Neoplastic Transformation and Cancer Stem Cells by Carbon Nanotubes

描述(申请人提供)：纳米技术有望成为下一次工业革命，并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。这项建议专门针对慢性肺部暴露后碳纳米管(CNT)的致癌效应。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的病理，但其潜在的机制和关键的致病因素尚不清楚，这限制了人类风险评估和疾病预防。我们推测，人肺上皮细胞长期暴露于碳纳米管可通过复杂的机制诱导恶性转化和癌变，包括P53基因异常、肿瘤干细胞(CSC)和上皮细胞间充质转化(EMT)的诱导。我们还提出，表征这些生物学变化的组合生物标记物可以预测碳纳米管诱导的癌症发生。提出了三个具体目标。在目标1中，我们将测试p53异常在碳纳米管致癌中的要求，并确定控制碳纳米管致癌的关键物理化学性质。目的2研究CSC在CNT致癌中的作用，确定CSC在CNT致癌反应中的独特标志物。目的3将描述EMT网络的特征，并确定其在CSC获得和CNT癌变中的作用。我们将确定预测CNT癌变的组合生物标记物，并验证它们在肺原位异种移植模型中的临床前应用。我们的预期是，在 本项目的结论是，我们将确定碳纳米管致癌的生物标志物，并确定决定碳纳米管致癌性的关键物理化学因素。这项工作之所以重要，是因为它将对碳纳米管致癌风险评估和预防以及安全纳米技术的发展产生整体影响。我们预计影响将是广泛的，因为该项目的发现非常适用于各种纳米材料。这项拟议的工作具有创新性，因为它结合了CSC和EMT的新概念，揭示了碳纳米管诱发癌症的潜在机制，这些机制目前在很大程度上是未知的。此外，该项目中开发的实验模型，如慢性暴露和肺原位异种移植模型，可以作为目前缺乏和迫切需要的纳米材料致癌性测试的预测性筛选工具。

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.