Nano-Scaled Particles of Titanium Dioxide Convert Benign Mouse Fibrosarcoma Cells into Aggressive Tumor Cells
Nano-Scaled Particles of Titanium Dioxide Convert Benign Mouse Fibrosarcoma Cells into Aggressive Tumor Cells
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DOI：
10.2353/ajpath.2009.080900
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发表时间：
2009-11-01
影响因子：
6
通讯作者：
Okada, Futoshi
中科院分区：
文献类型：
--
作者：
Onuma, Kunishige;Sato, Yu;Okada, Futoshi
纳米颗粒在商业和医药产品中普遍存在;然而，纳米材料对致癌作用的贡献仍不清楚。因此，我们研究了纳米二氧化钛（TiO 2）对致瘤性差和非转移性QR-32纤维肉瘤细胞的影响。我们发现，皮下共移植QR-32细胞和纳米级TiO 2（未涂层（TiO 2 -1，亲水性）或涂有硬脂酸（TiO 2 -2，疏水性））的小鼠不会形成肿瘤。然而，QR-32细胞在注射到先前植入TiO 2 -1而非TiO 2 -2的部位后变成致瘤性的，并且这些发展中的肿瘤获得转移表型。TiO 2 -1和TiO 2 -2处理之间在组织学或炎性细胞因子mRNA表达方面均未观察到差异。然而，TiO 2 -2，而不是TiO 2 -1，在无细胞条件下产生高水平的活性氧（ROS）。尽管TiO 2 -1和TiO 2 -2均导致细胞内ROS形成，但TiO 2 -2引起更强的反应，导致对QR-32细胞的细胞毒性。此外，TiO 2 -2，而不是TiO 2 -1导致核间隙和多核细胞的发展。在TiO 2毒性中存活的细胞获得了致瘤表型。添加抗氧化剂N-乙酰-L-半胱氨酸可抑制TiO 2诱导的ROS形成及其相关的细胞损伤。这些结果表明，纳米TiO 2具有通过在靶细胞中产生ROS将良性肿瘤细胞转化为恶性肿瘤细胞的潜力。(Am J Pathol 2009，175.2171-2183，DOI：10.2353/ajpath/2009.080900）
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)