Qin Fengxian, Liu Xiaoyong, Chen Jifei, Huang Shishun, Wei Wei, Zou Yan, Liu Xuexiang, Deng Kaifeng, Mo Shanying, Chen Jianming, Chen Xiaoli, Huang Yujie, Liang Weijun
Medical Science Laboratory, the Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, P. R. China 545005.
Department of Clinical Laboratory, Liuzhou Municipal Liutie Center Hospital, Liuzhou, Guangxi, P. R. China 545007.
J Cancer. 2020 Feb 14;11(9):2580-2592. doi: 10.7150/jca.38179. eCollection 2020.
Tumor associated neutrophils (TANs) play important roles in the progress of CRC. Since tumor microenvironments could influence the phenotypes of TANs, altering the tumor microenvironment to polarize the phenotype of TANs may be a new strategy for tumor treatment. This study aims to investigate the effect of anti-TGF-β on the polarization of TANs from a pro-tumor phenotype towards an anti-tumor phenotype in CRC. In this work, CRC patients had more infiltration of TANs and higher expression of TGF-β in CRC tissue when compared with the controls. , SW480 cells were co-cultured with primed neutrophils, which simulated the TANs in the tumor microenvironment, and TGF-β was blocked by anti-TGF-β (1D11) in order to polarize TANs. Anti-TGF-β treatment increased the cytotoxicity of TANs and decreased the metastatic chemoattractants secreted by TANs, and ultimately increased the apoptosis of CRC cells significantly while remarkably suppressing the migration of tumor cells. The changes of signaling pathways in the TANs and tumor cells were explored. The results showed that anti-TGF-β attenuated CRC may be partly mediated by suppression of PI3K/AKT signaling pathways in TANs and partly mediated by suppression of TGF-β/Smad signaling pathways in tumor cells. Furthermore, the tumor in the mice treated with 1D11 was obviously smaller and had reverse tumorigenesis compared with the controls, while neutrophil depletion reduced the anti-tumor effect of 1D11. Our data suggest that anti-TGF-β attenuates tumor growth via the polarization of TANs to an anti-tumor phenotype in CRC, which provides new strategies for CRC treatment.
肿瘤相关中性粒细胞（TANs）在结直肠癌（CRC）进展中发挥重要作用。由于肿瘤微环境可影响TANs的表型，改变肿瘤微环境以使TANs表型极化可能是一种新的肿瘤治疗策略。本研究旨在探讨抗转化生长因子-β（TGF-β）对CRC中TANs从促肿瘤表型向抗肿瘤表型极化的影响。在本研究中，与对照组相比，CRC患者的CRC组织中TANs浸润更多且TGF-β表达更高。将SW480细胞与预激活的中性粒细胞共培养，后者模拟肿瘤微环境中的TANs，并使用抗TGF-β（1D11）阻断TGF-β以极化TANs。抗TGF-β处理增加了TANs的细胞毒性，降低了TANs分泌的转移趋化因子，最终显著增加了CRC细胞的凋亡，同时显著抑制了肿瘤细胞的迁移。探讨了TANs和肿瘤细胞中信号通路的变化。结果表明，抗TGF-β减轻CRC可能部分是通过抑制TANs中的PI3K/AKT信号通路，部分是通过抑制肿瘤细胞中的TGF-β/Smad信号通路介导的。此外，与对照组相比，用1D11处理的小鼠体内肿瘤明显更小且有肿瘤逆转，而中性粒细胞耗竭降低了1D11的抗肿瘤作用。我们的数据表明，抗TGF-β通过将CRC中的TANs极化为抗肿瘤表型来减轻肿瘤生长，这为CRC治疗提供了新策略。
