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.

Public Health Relevance

Nanotechnology presents enormous opportunities to create new and better products for commercial and biomedical applications. However, the adverse health effects of nanomaterials are unclear which limits the development and widespread use of nanotechnology. The main objectives of this project are to 1) determine the potential carcinogenic effects of carbon nanotubes (CNT), 2) identify key characteristics of CNT that contribute to their carcinogenicity, 3) determine the underlying mechanisms of carcinogenesis, and 4) identify specific biomarkers for early detection and prevention of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES022968-01A1
Application #
8691555
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Nadadur, Srikanth
Project Start
2014-05-06
Project End
2019-02-28
Budget Start
2014-05-06
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$334,875
Indirect Cost
$109,875
Name
West Virginia University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506
Wang, Peng; Voronkova, Maria; Luanpitpong, Sudjit et al. (2017) Induction of Slug by Chronic Exposure to Single-Walled Carbon Nanotubes Promotes Tumor Formation and Metastasis. Chem Res Toxicol 30:1396-1405
Luanpitpong, Sudjit; Chanthra, Nawin; Janan, Montira et al. (2017) Inhibition of O-GlcNAcase sensitizes apoptosis and reverses bortezomib resistance in mantle cell lymphoma through modification of truncated Bid. Mol Cancer Ther :
Wagner, Alixandra; Eldawud, Reem; White, Andrew et al. (2017) Toxicity evaluations of nanoclays and thermally degraded byproducts through spectroscopical and microscopical approaches. Biochim Biophys Acta 1861:3406-3415
Powan, Phattrakorn; Luanpitpong, Sudjit; He, Xiaoqing et al. (2017) Detachment-induced E-cadherin expression promotes 3D tumor spheroid formation but inhibits tumor formation and metastasis of lung cancer cells. Am J Physiol Cell Physiol 313:C556-C566
Stueckle, Todd A; Davidson, Donna C; Derk, Ray et al. (2017) Effect of surface functionalizations of multi-walled carbon nanotubes on neoplastic transformation potential in primary human lung epithelial cells. Nanotoxicology 11:613-624
Stueckle, Todd A; Davidson, Donna C; Derk, Raymond et al. (2017) Evaluation of tumorigenic potential of CeO2 and Fe2O3 engineered nanoparticles by a human cell in vitro screening model. NanoImpact 6:39-54
Voronkova, Maria A; Luanpitpong, Sudjit; Rojanasakul, Liying Wang et al. (2017) SOX9 Regulates Cancer Stem-Like Properties and Metastatic Potential of Single-Walled Carbon Nanotube-Exposed Cells. Sci Rep 7:11653
He, Xiaoqing; Wang, Liying; Riedel, Heimo et al. (2017) Mesothelin promotes epithelial-to-mesenchymal transition and tumorigenicity of human lung cancer and mesothelioma cells. Mol Cancer 16:63
He, Xiaoqing; Despeaux, Emily; Stueckle, Todd A et al. (2016) Role of mesothelin in carbon nanotube-induced carcinogenic transformation of human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 311:L538-49
Luanpitpong, Sudjit; Wang, Liying; Castranova, Vincent et al. (2016) Induction of cancer-associated fibroblast-like cells by carbon nanotubes dictates its tumorigenicity. Sci Rep 6:39558

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