Pivotal role of CXCR3 in melanoma cell metastasis to lymph nodes
Pivotal role of CXCR3 in melanoma cell metastasis to lymph nodes
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DOI：
10.1158/0008-5472.can-03-1757
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发表时间：
2004-06-01
期刊：
影响因子：
11.2
通讯作者：
Taketo, MM
中科院分区：
文献类型：
--
作者：
Kawada, K;Sonoshita, M;Taketo, MM
趋化因子及其受体在白细胞运输中起关键作用，也与癌症转移到特定器官有关。本研究表明，小鼠B16F10黑色素瘤细胞组成性地表达趋化因子受体CXCR3，其配体CXCL9/Mig、CXCL10/IP-10和CXC11/I-TAC在体外诱导细胞反应，如肌动蛋白聚合、迁移、侵袭和细胞存活。为了确定CXCR3是否在淋巴结转移中发挥作用，我们通过反义RNA构建了CXCR3表达降低的B16F10细胞，并研究了sc接种到同源宿主C57BL/6小鼠后的转移活性。与亲代或空载体转导细胞相比，这些细胞向LNs转移的频率明显降低，接近15% （P < 0.05）。另一方面，用完全弗氏佐剂预处理小鼠，使引流淋巴结中CXCL9和CXCL10水平升高，使B16F10细胞向病灶更大的淋巴结转移的频率增加2.5 ~ 3.0倍（P < 0.05）。重要的是，当B16F10细胞中的CXCR3表达被反义RNA降低或小鼠被针对CXCL9和CXCL10的特异性抗体处理时，这种转移的刺激在很大程度上被抑制。我们还证明了CXCR3在几种人类黑色素瘤细胞系以及原发性人类黑色素瘤组织中表达（9个样本中的5个）。这些结果表明，CXCR3抑制剂可能是治疗LN转移（包括黑色素瘤）的有希望的治疗药物。
Chemokines and their receptors play key roles in leukocyte trafficking and are also implicated in cancer metastasis to specific organs. Here we show that mouse B16F10 melanoma cells constitutively express chemokine receptor CXCR3, and that its ligands CXCL9/Mig, CXCL10/IP-10, and CXC11/I-TAC induce cellular responses in vitro, such as actin polymerization, migration, invasion, and cell survival. To determine whether CXCR3 could play a role in metastasis to lymph nodes (LNs), we constructed B16F10 cells with reduced CXCR3 expression by antisense RNA and investigated their metastatic activities after s.c. inoculations to syngeneic hosts, C57BL/6 mice. The metastatic frequency of these cells to LNs was markedly reduced to similar to15% (P < 0.05) compared with the parental or empty vector-transduced cells. On the other hand, pretreatment of mice with complete Freund's adjuvant increased the levels of CXCL9 and CXCL10 in the draining LNs, which caused 2.5-3.0-fold increase (P < 0.05) in the metastatic frequency of B16F10 cells to the nodes with much larger foci. Importantly, such a stimulation of metastasis was largely suppressed when CXCR3 expression in B16F10 cells was reduced by antisense RNA or when mice were treated with specific antibodies against CXCL9 and CXCL10. We also demonstrate that CXCR3 is expressed on several human melanoma cell lines as well as primary human melanoma tissues (5 of 9 samples tested). These results suggest that CXCR3 inhibitors may be promising therapeutic agents for treatment of LN metastasis, including that of melanoma.