Silencing of TLR4 Increases Tumor Progression and Lung Metastasis in a Murine Model of Breast Cancer
Silencing of TLR4 Increases Tumor Progression and Lung Metastasis in a Murine Model of Breast Cancer
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DOI：
10.1245/s10434-012-2595-9
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发表时间：
2013-12-01
影响因子：
3.7
通讯作者：
Redmond, H. Paul
中科院分区：
文献类型：
--
作者：
Ahmed, Abubakr;Wang, Jiang Huai;Redmond, H. Paul
背景Toll样受体4（TLR 4）是参与宿主防御微生物感染的模式识别受体家族的成员。很少有研究调查TLR 4与癌症之间的联系。因此，我们解决了TLR 4在宿主免疫系统和癌细胞中关于其对乳腺癌进展和转移的影响的作用。将6-8周龄的成年雌性Balb/c小鼠分成三组。第1组为野生型和TLR 4（-/-）小鼠各15只，第2组为野生型小鼠，分别接种4 T1细胞（n = 15）、转染TLR 4慢病毒的4 T1细胞（n = 15）或对照慢病毒（n = 15）;第3组，15只TLR 4（-/-）小鼠接种转染TLR 4慢病毒的4 T1细胞。在第2-5周期间用卡尺测量侧腹肿瘤体积。然后人道处死动物并计数肉眼可见的肺结节数量。与野生型小鼠相比，在用4 T1细胞接种TLR 4（-/-）小鼠后的第2、3和4周，肿瘤体积显著增加（p < 0.05）。转移性肺结节的数量在TLR 4（-/-）小鼠中显著更高（p < 0.05），并且与野生型小鼠相比，携带肿瘤的TLR 4（-/-）小鼠的存活率显著降低（p = 0.004）。4 T1细胞TLR 4的敲低导致肺转移的相对减少，尽管没有达到统计学意义。在该鼠转移性乳腺肿瘤模型中，TLR 4在宿主水平发挥防御作用，在癌细胞水平发挥负作用。进一步评估TLR 4在乳腺癌中的作用是必要的。
Background. Toll-like receptor 4 (TLR4) is a member of a family of pattern recognition receptors that are involved in the host defense against microbial infection. Little research has investigated the link between TLR4 and cancer. We thus addressed the effect of TLR4 in both the host immune system and cancer cells with regard to its effect on breast cancer progression and metastasis.Methods. Adult female Balb/c mice aged 6-8 weeks were divided into three groups. In group 1, 15 each wild-type and TLR4(-/-) mice were inoculated with 4T1 cells; in group 2, wild-type mice were inoculated with 4T1 cells (n = 15), 4T1 cells transduced with TLR4 lentivirus (n = 15) or with control lentivirus (n = 15); and in group 3, 15 TLR4(-/-) mice were inoculated with 4T1 cells transduced with TLR4 lentivirus. Flank tumor volume was measured with calipers during weeks 2-5. Animals were then humanely killed and the number of macroscopic lung nodules counted.Results. There was a significant increase in tumor volume in weeks 2, 3 and 4 after inoculation of TLR4(-/-) mice with 4T1 cells compared with wild-type mice (p < 0.05). The number of metastatic lung nodules was significantly higher in TLR4(-/-) mice (p < 0.05), and survival of tumor-bearing TLR4(-/-) mice was substantially reduced compared with wild-type mice (p = 0.004). Knockdown of TLR4 from the 4T1 cells led to a relative reduction in lung metastasis, although it did not reach statistical significance.Conclusions. TLR4 exerts both a defensive role at the host level and a negative role at the cancer cell level in this murine metastatic breast tumor model. Further evaluation of the role of TLR4 in breast cancer is warranted.