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.
Highlights
Source Catalog reference Synthesis methoda Primary functionalitya Dry mean widtha Dry mean lengtha % elemental carbona % iron impurityb Other metal impuritiesb
Dividing this dose by the average alveolar surface area in mice (~500 cm2)[27] indicates the in vitro carbon nanotubes (CNTs) surface area dose of 0.08 μg/cm[2], which is equivalent to a human lung burden for 8 h/day over 2 years at 400 μg/m328 or about 76 years at 10 μg/m329
To test whether CNTs could induce cancer-associated fibroblasts (CAFs) and promote tumor formation, we investigated the effect of CNTs on human lung fibroblasts (LFs) with respect to their ability to induce CAFs and to support tumor growth induced by human lung carcinoma cells and CNT-transformed lung epithelial cells
Summary
Source Catalog reference Synthesis methoda Primary functionalitya Dry mean width (nm)a Dry mean length (μm)a % elemental carbona % iron impurityb Other metal impuritiesb. We investigated the effect of CNTs on cancer-associated fibroblasts (CAFs), a key component of the tumor microenvironment known to regulate tumor growth[18,19]. Because of their importance in tumorigenesis and metastasis, CAFs have been investigated as a novel target of cancer therapy and as a key contributor of the carcinogenic effect of various agents. Podoplanin was identified as a key protein responsible for the tumor-promoting effect of CNT-induced CAFs and thereby could be a novel candidate biomarker for initial screening of the carcinogenicity of CNTs and related nanomaterials
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