title: Induction of cancer-associated fibroblast-like cells by carbon nanotubes dictates its tumorigenicity.
abstract: Tumor microenvironment has been recognized as a key determinant of tumor formation and metastasis, but how tumor microenvironment is affected by nanomaterials is essentially unknown. Here, we investigated whether carbon nanotubes (CNTs), a widely used nanomaterial with known carcinogenic potential, can affect cancer-associated fibroblasts (CAFs), which are a key component of tumor microenvironment that provides necessary support for tumor growth. We show for the first time that single-walled CNT and to a lesser extent multi-walled and its COOH-functionalized form induced CAF-like cells, which are non-tumorigenic in animals, but promote tumor growth of human lung carcinoma and CNT-transformed lung epithelial cells. The mechanism by which CNT-induced CAF-like cells promote tumor growth involved the acquisition of cancer stem cells (CSCs) in cancer population. Gene knockdown experiments showed that an expression of podoplanin on CAF-like cells is essential for their effects, indicating the functional role of CAF-like cells and podoplanin in CNT tumorigenic process. Our findings unveil a novel mechanism of CNT-induced carcinogenesis through the induction of CAF-like cells that support CSCs and drive tumor formation. Our results also suggest the potential utility of podoplanin as a mechanism-based biomarker for rapid screening of carcinogenicity of CNTs and related nanomaterials for their safer design.
authors.affiliation: Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.|Pharmaceutical and Pharmacological Sciences Program, West Virginia University, WV 26506, USA.
authors.forename: Sudjit
authors.initials: S
authors.lastname: Luanpitpong
authors.affiliation: Allergy and Clinical Immunology Branch, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA.
authors.forename: Liying
authors.initials: L
authors.lastname: Wang
authors.affiliation: Pharmaceutical and Pharmacological Sciences Program, West Virginia University, WV 26506, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Castranova
authors.affiliation: Department of Chemical Engineering, West Virginia University, WV 26506, USA.
authors.forename: Cerasela Zoica
authors.initials: CZ
authors.lastname: Dinu
authors.affiliation: Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
authors.forename: Surapol
authors.initials: S
authors.lastname: Issaragrisil
authors.affiliation: Natural Science Division, Alderson Broaddus University, Philippi, WV 26416, USA.
authors.forename: Yi Charlie
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Pharmaceutical and Pharmacological Sciences Program, West Virginia University, WV 26506, USA.|West Virginia University Cancer Institute, West Virginia University, WV 26506, USA.
authors.forename: Yon
authors.initials: Y
authors.lastname: Rojanasakul
mesh_terms: D000071916:AC133 Antigen / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D000072645:Cancer-Associated Fibroblasts / Q000166:cytology*; D002452:Cell Count; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D004847:Epithelial Cells / Q000166:cytology; D006801:Humans; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D037742:Nanotubes, Carbon / Q000737:chemistry*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology; D015398:Signal Transduction; D059016:Tumor Microenvironment; D000098853:Podoplanin
chemical_list: D000071916:AC133 Antigen; D014408:Biomarkers, Tumor; D008562:Membrane Glycoproteins; D037742:Nanotubes, Carbon; C117468:PDPN protein, human; D000098853:Podoplanin; C000606023:PROM1 protein, human