Induction of Neoplastic Transformation and Cancer Stem Cells by Carbon Nanotubes

描述（申请人提供）：纳米技术作为下一次工业革命具有很大的前景，预计将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的不良影响的生化机制和物理化学因素，实现安全的纳米技术。该提案专门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，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，但潜在的机制和关键因素尚不清楚，这限制了人类风险评估和疾病预防。我们假设，慢性暴露于CNT的人肺上皮细胞诱导恶性转化和癌变通过复杂的机制，涉及p53失调和诱导癌症干细胞（CSC）和上皮间质转化（EMT）。我们还提出，组合生物标志物的特征，这些生物学变化可以预测CNT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致癌作用中p53失调的要求，并确定控制CNT致癌性的关键理化性质。目的2研究CSC在CNT致癌中的作用，并确定CNT致癌反应的独特CSC标志物。目的3将表征EMT网络，并确定其在CSC收购和CNT致癌作用。我们将鉴定组合生物标志物以预测CNT致癌作用并验证其在肺原位异种移植模型中的临床前使用。我们的期望是，在 本项目结束后，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。这项工作是重要的，因为它将对风险评估和预防CNT致癌和安全纳米技术的发展产生整体影响。我们预计其影响将是广泛的，因为该项目的发现高度适用于各种纳米材料。这项工作是创新的，因为它结合了CSC和EMT的新概念，揭示了CNT诱导的致癌作用的潜在机制，目前在很大程度上是未知的。此外，本项目开发的实验模型，如慢性暴露和肺原位异种移植模型，可用作目前缺乏和急需的纳米材料致癌性测试的预测筛选工具。

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.