Carbon nanomaterial-induced malignant transformation and lung carcinogenesis

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PI: Rojanasakul, Yon Proposal Number: 1434503Institution: West Virginia University Research CorporationTitle: Carbon nanomaterial-induced malignant transformation and lung carcinogenesis Engineered nanomaterials, including carbon nanotubes (CNTs), have increasingly been used for a variety of applications. However, the risk of adverse health effects, such as from the potential carcinogenicity of CNTs are not understood. The PI, and Co-PI, have developed a chronic exposure model in which human lung epithelial cells, a major cellular target of CNT carcinogenesis, are exposed, over long-term, to low-dose physiologically relevant concentrations of CNTs. The PI and Co-PI will examine how the physicochemical properties (length, metal impurity, surface charge, surface chemical modifications, etc) may induce malignant transformations in cells, look for potential biomarkers, and investigate the role of those biomarkers in induced transformations and tumors. If successful, this approach can provide experimental models and assay methods that reliably predict CNT carcinogenicity, while also establishing specific biomarkers for CNT-induced carcinogenesis. This, in turn will advance both safer-by-design strategies and worker protection issues. Public presentations and summary reports, revealing the fundamental findings from this project in nontechnical terms, will be posted on the West Virginia University, NanoSAFE, and NIOSH websites, while the intended outreach efforts include underrepresented groups. In this proposal, the PIs hypothesize that CNT carcinogenicity is dependent on their physicochemical properties and ability to induce malignant transformation of target lung cells through mesothelin (MSLN, a known biomarker for asbestos induced cancer) and matrix metalloproteinase (MMP-2) dependent mechanisms. To verify this hypothesis, the PIs will break down the investigations into 3 aims: 1) Develop in vitro models to predict CNT carcinogenicity, and determine if the induction of malignant transformation and tumor formation is predictive of in vivo tumorigenic responses; 2) Determine the role of MSLN in CNT-induced transformations and tumors, and elucidate the underlying mechanisms; and 3) Evaluate the use of MSLN and MMP-2 as combination biomarkers to predict CNT carcinogenicity and determine the effect of CNT on MSLN and MMP-2 induction to see if such induction is predictive of in vivo tumorigenic responses. This is an innovative proposal that addresses an important question, the relationship of nanomaterial properties to long-term human disease. Additional strengths include the use of archived reference materials and realistic doses that can be compared to in vivo exposures. In addition, the use of shared particle samples is essential for both replication and for follow-up studies.