Organ-specific inhibition of metastatic colon carcinoma by CXCR3 antagonism.
Organ-specific inhibition of metastatic colon carcinoma by CXCR3 antagonism.
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DOI：
10.1038/sj.bjc.6605078
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发表时间：
2009-06-02
影响因子：
8.8
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中科院分区：
文献类型：
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肝和肺转移是结直肠癌（CRC）相关死亡的主要原因。最近的研究表明，协调造血细胞运动的CXCR3/趋化因子相互作用与恶性肿瘤的转移过程有关，包括CRC细胞向淋巴结的转移。然而，迄今为止，CXCR3在结直肠癌肝和肺转移中的作用尚未得到解决。为了确定CXCR3受体是否调节CRC细胞的恶性相关特性，我们将表达CXCR3的人（HT29细胞）和小鼠（C26细胞）CRC细胞系分别注射到免疫缺陷小鼠和免疫正常小鼠体内，使其发生肝脏和肺转移，并使用小分子量拮抗剂AMG487评估CXCR3阻断的效果。在体外，CXCR3通过其同源配体对人和小鼠CRC细胞的激活诱导了迁移和生长反应，这两种活性都被AMG487消除。在体内，AMG487预防性或治疗性治疗的系统性CXCR3拮抗作用可显著抑制人和小鼠CRC细胞在肺内的植入和生长，而不影响肝内的植入和生长。此外，与肝肿瘤相比，我们测量了肺结节中CXCR3和配体表达水平的增加。总之，我们的研究结果表明，在两种小鼠肿瘤模型中，CXCR3受体的同源配体激活促进了CRC细胞在肺组织内的植入和进展，抑制该轴可减少CRC的肺转移。
Liver and lung metastases are the predominant cause of colorectal cancer (CRC)-related mortality. Recent research has indicated that CXCR3/chemokines interactions that orchestrate haematopoetic cell movement are implicated in the metastatic process of malignant tumours, including that of CRC cells to lymph nodes. To date, however, the contribution of CXCR3 to liver and lung metastasis in CRC has not been addressed. To determine whether CXCR3 receptors regulate malignancy-related properties of CRC cells, we have used CXCR3-expressing CRC cell lines of human (HT29 cells) and murine (C26 cells) origins that enable the development of liver and lung metastases when injected into immunodeficient and immunocompetent mice, respectively, and assessed the effect of CXCR3 blockade using AMG487, a small molecular weight antagonist. In vitro, activation of CXCR3 on human and mouse CRC cells by its cognate ligands induced migratory and growth responses, both activities being abrogated by AMG487. In vivo, systemic CXCR3 antagonism by preventive or curative treatments with AMG487 markedly inhibited the implantation and the growth of human and mouse CRC cells within lung without affecting that in the liver. In addition, we measured increased levels of CXCR3 and ligands expression within lung nodules compared with liver tumours. Altogether, our findings indicate that activation of CXCR3 receptors by its cognate ligands facilitates the implantation and the progression of CRC cells within lung tissues and that inhibition of this axis decreases pulmonary metastasis of CRC in two murine tumour models.