Induction of Neoplastic Transformation and Cancer Stem Cells by Carbon Nanotubes

描述（由申请人提供）：纳米技术作为下一次工业革命具有巨大的前景，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接触对健康不利影响的生化机制和理化因素，实现安全的纳米技术。本提案专门针对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，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，碳纳米管可以诱导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。我们假设人类肺上皮细胞长期暴露于碳纳米管诱导恶性转化和癌变的复杂机制涉及p53失调和诱导癌症干细胞（CSC）和上皮间充质转化（EMT）。我们还提出，表征这些生物学变化的联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Aim 1中，我们将测试p53失调在碳纳米管癌变中的要求，并确定控制碳纳米管致癌性的关键理化性质。目的2将研究CSC在碳纳米管癌变中的作用，并确定碳纳米管癌变反应的独特CSC标志物。目的3将表征EMT网络并确定其在CSC获得和CNT癌变中的作用。我们将确定联合生物标志物来预测碳纳米管癌变，并验证其在肺原位异种移植模型中的临床前应用。我们的期望是

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.