Blockade of CXCR4 in oral squamous cell carcinoma inhibits lymph node metastases
Blockade of CXCR4 in oral squamous cell carcinoma inhibits lymph node metastases
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DOI：
10.1016/j.ejca.2010.09.028
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发表时间：
2011-02-01
影响因子：
8.4
通讯作者：
Miyamoto, Youji
中科院分区：
文献类型：
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作者：
Uchida, Daisuke;Onoue, Tomitaro;Miyamoto, Youji
我们先前已经证明，基质细胞衍生因子-1（SDF-1; CXCL 12）/CXCR 4系统参与口腔鳞状细胞癌（OSCC）淋巴结转移的建立。在这项研究中，我们研究了CXCR 4的阻断是否抑制B88 OSCC细胞的淋巴结转移。这些细胞具有功能性CXCR 4，并具有体内转移至淋巴结的潜力。在引入表达针对CXCR 4的短发夹小干扰RNA（shRNA）的载体后，我们分离出三个克隆（shCXCR 4 -16、-17和-21），其显示CXCR 4 mRNA表达降低。这些克隆还具有降低的CXCR 4蛋白水平，并显示响应于SDF-1的钙通量和细胞迁移的损伤。将这些细胞原位接种到裸鼠咬肌中。与接种对照细胞的小鼠相比，接种shCXCR 4 -17细胞的小鼠的淋巴结转移、体重减轻和肿瘤体积显著受到抑制。CXCR 4拮抗剂1，1 '-1，4-亚苯基双（亚甲基）]双-1，4，8，11-四氮杂环十四烷八盐酸盐（AMD 3100）可显著抑制SDF-1诱导的B88细胞迁移。皮下注射AMD 3100可明显抑制B88细胞原位接种于裸小鼠咬肌的淋巴结转移。此外，针对CXCR 4的shRNA或AMD 3100处理可抑制SDF-1引起的白细胞介素（IL）-6和IL-8的产生。这些结果表明，阻断CXCR 4可能是一种有效的抗转移治疗对淋巴结转移的情况下，CXCR 4相关的口腔鳞癌。(C)2010爱思唯尔有限公司版权所有。
We have previously demonstrated that a stromal cell-derived factor-1 (SDF-1; CXCL12)/CXCR4 system is involved in the establishment of lymph node metastasis in oral squamous cell carcinoma (OSCC). In this study, we investigated whether the blockade of CXCR4 inhibits lymph node metastasis in B88 OSCC cells. These cells harbour a functional CXCR4 and have the potential to metastasise to the lymph node in vivo. Following introduction of a vector that expresses short hairpin small interfering RNA (shRNA) against CXCR4, we isolated three clones (shCXCR4-16, -17 and -21) that showed decreased expression of CXCR4 mRNA. These clones also had reduced CXCR4 protein levels and showed impairments in calcium flux and cell migration in response to SDF-1. These cells were orthotopically inoculated into the masseter muscle of nude mice. Lymph node metastases, loss in body weight and tumour volumes were significantly inhibited in mice inoculated with shCXCR4-17 cells compared to mice inoculated with control cells. SDF-1-induced migration of B88 cells was significantly inhibited in vitro by the treatment with 1,1'-1[4-phenylenebis(methylene)]bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride (AMD3100), a CXCR4 antagonist. Subcutaneous administration of AMD3100 significantly inhibited the lymph node metastases of B88 cells when they were orthotopically inoculated into the masseter muscle of nude mice. Moreover, the enhanced production of interleukin (IL)-6 and IL-8 in response to SDF-1 was inhibited by shRNA against CXCR4 or by treatment with AMD3100. These results suggest that blockade of CXCR4 may be a potent anti-metastatic therapy against lymph node metastases in cases of CXCR4-related OSCC. (C) 2010 Elsevier Ltd. All rights reserved.