CXCL4 mediates tumor regrowth after chemotherapy by suppression of antitumor immunity
CXCL4 mediates tumor regrowth after chemotherapy by suppression of antitumor immunity
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DOI：
10.1080/15384047.2015.1095404
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发表时间：
2015-10
影响因子：
3.6
通讯作者：
Yang Zhang;Jin Gao;Xia Wang;Shaorong Deng;Hao Ye;W. Guan;Mingyuan Wu;Shunying Zhu;Yan Yu;W. Han
中科院分区：
文献类型：
--
作者：
Yang Zhang;Jin Gao;Xia Wang;Shaorong Deng;Hao Ye;W. Guan;Mingyuan Wu;Shunying Zhu;Yan Yu;W. Han
结直肠癌化疗后复发是其高死亡率的主要原因。我们认为，阐明荷瘤小鼠化疗后肿瘤再生长的机制可能会为癌症患者的肿瘤复发提供新的见解。我们首先报告了一种趋化因子CXCL4的鉴定，它在肿瘤化疗后再生长的分子机制中发挥重要作用。用小鼠结肠癌CT26细胞建立同基因移植瘤模型，并用5-FU治疗。全基因组基因表达分析确定CXCL4在肿瘤模型中瞬时上调。CXCL4的全身性过表达在体内加速了肿瘤的生长，但在体外没有。相反，抗CXCL4单抗(CXCL4-MAb)在免疫活性良好的小鼠体内延缓了5-FU治疗后的肿瘤再生长，但对裸鼠没有影响。CXCL4-MAb治疗可提高肿瘤床局部干扰素-γ和GRAN-b基因的表达水平，增强CTL对CT26细胞的杀伤作用。因此，结肠癌细胞在对5-FU的细胞毒应激反应中产生高水平的CXCL4，从而抑制抗肿瘤免疫，从而使残留的癌细胞在化疗后有利于重新生长。我们的发现为开发旨在提高化疗后抗肿瘤免疫的治疗药物提供了一个新的靶点。
The recurrence of colorectal cancer after chemotherapy is the leading cause of its high mortality. We propose that elucidating the mechanisms of tumor regrowth after chemotherapy in tumor-bearing mice may provide new insights into tumor relapse in cancer patients. We firstly report the identification of a chemokine, CXCL4, that plays an important role in the molecular mechanism of cancer regrowth after chemotherapy. A syngenic transplantation tumor model was established with murine colon cancer CT26 cells and treated with 5-FU. Genome-wide gene expression analysis determined that CXCL4 was transiently upregulated in the tumor model. Systemic overexpression of CXCL4 accelerated cancer growth in vivo, but not in vitro. Conversely, the anti-CXCL4 monoclonal antibody (CXCL4-mab) retarded tumor-regrowth after 5-FU treatment in immune-competent mice, but not nude mice. The CXCL4-mab treatment increased the local expression levels of IFN-γ and Gran-b genes in the tumor-bed, and elevated the function of CTLs against CT26 cells. Thus, the colon cancer cells in responding to the cytotoxic stress of 5-FU produce a high level of CXCL4, which suppresses antitumor immunity to confer the residual cancer cells an advantage for regrowth after chemotherapy. Our findings provide a novel target for developing therapeutics aiming to increase antitumor immunity after chemotherapy.