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 (TiO(2)) on poorly tumorigenic and nonmetastatic QR-32 fibrosarcoma cells. We found that mice that were cotransplanted subcutaneously with QR-32 cells and nano-sized TiO(2), either uncoated (TiO(2)-1, hydrophilic) or coated with stearic acid (TiO(2)-2, hydrophobic), did not form tumors. However, QR-32 cells became tumorigenic after injection into sites previously implanted with TiO(2)-1, but not TiO(2)-2, and these developing tumors acquired metastatic phenotypes. No differences were observed either histologically or in inflammatory cytokine mRNA expression between TiO(2)-1 and TiO(2)-2 treatments. However, TiO(2)-2, but not TiO(2)-1, generated high levels of reactive oxygen species (ROS) in cell-free conditions. Although both TiO(2)-1 and TiO(2)-2 resulted in intracellular ROS formation, TiO(2)-2 elicited a stronger response, resulting in cytotoxicity to the QR-32 cells. Moreover, TiO(2)-2, but not TiO(2)-1, led to the development of nuclear interstices and multinucleate cells. Cells that survived the TiO(2) toxicity acquired a tumorigenic phenotype. TiO(2)-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 TiO(2) has the potential to convert benign tumor cells into malignant ones through the generation of ROS in the target cells.
Onuma
Kunishige
K
Department of Biochemistry and Molecular Biology, Yamagata University, Japan.
Sato
Yu
Y
Ogawara
Satomi
S
Shirasawa
Nobuyuki
N
Kobayashi
Masanobu
M
Yoshitake
Jun
J
Yoshimura
Tetsuhiko
T
Iigo
Masaaki
M
Fujii
Junichi
J
Okada
Futoshi
F
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D005354:Fibrosarcoma / Q000378:metabolism / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D009361:Neoplasm Invasiveness / Q000473:pathology; D010316:Particle Size; D017382:Reactive Oxygen Species / Q000378:metabolism; D013947:Thymosin / Q000235:genetics / Q000378:metabolism; D014025:Titanium / Q000737:chemistry / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099201:Thymosin beta(4)
D000080242:8-Hydroxy-2'-Deoxyguanosine; D016207:Cytokines; D003849:Deoxyguanosine; D015232:Dinoprostone; D036341:Intercellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D013947:Thymosin; D014025:Titanium; D042461:Vascular Endothelial Growth Factor A; D000099201:Thymosin beta(4); C009495:titanium dioxide