Nano-Scaled Particles of Titanium Dioxide Convert Benign Mouse Fibrosarcoma Cells into Aggressive Tumor Cells

Nanoparticles are prevalent in both commercial and medicinal products; however, the contribution of nanomaterials to carcinogenesis remains unclear. We therefore examined the effects of nano-sized titanium dioxide (TiO2) on poorly tumorigenic and nonmetastatic QR-32 fibrosarcoma cells. We found that mice that were cotransplanted subcutaneously with QR-32 cells and nano-sized TiO2, either uncoated (TiO2-1, hydrophilic) or coated with stearic acid (TiO2-2, hydrophobic), did not form tumors. However, QR-32 cells became tumorigenic after injection into sites previously implanted with TiO2-1, but not TiO2-2, and these developing tumors acquired metastatic phenotypes. No differences were observed either histologically or in inflammatory cytokine mRNA expression between TiO2-1 and TiO2-2 treatments. However, TiO2-2, but not TiO2-1, generated high levels of reactive oxygen species (ROS) in cell-free conditions. Although both TiO2-1 and TiO2-2 resulted in intracellular ROS formation, TiO2-2 elicited a stronger response, resulting in cytotoxicity to the QR-32 cells. Moreover, TiO2-2, but not TiO2-1 led to the development of nuclear interstices and multinucleate cells. Cells that survived the TiO2 toxicity acquired a tumorigenic phenotype. TiO2-induced ROS formation and its related cell injury were inhibited by the addition of antioxidant N-acetyl-L-cysteine. These results indicate that nano-sized TiO2 has the potential to convert benign tumor cells into malignant ones through the generation of ROS in the target cells. (Am J Pathol 2009, 175.2171-2183, DOI: 10.2353/ajpath/2009.080900)