CCR4 is a determinant of melanoma brain metastasis.
CCR4 is a determinant of melanoma brain metastasis.
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DOI：
10.18632/oncotarget.16076
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发表时间：
2017-05-09
期刊：
影响因子：
--
通讯作者：
Witz IP
中科院分区：
文献类型：
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作者：
Klein A;Sagi-Assif O;Meshel T;Telerman A;Izraely S;Ben-Menachem S;Bayry J;Marzese DM;Ohe S;Hoon DSB;Erez N;Witz IP
我们以前确定趋化因子受体CCR4作为黑色素瘤脑转移的分子特征的一部分。本研究的目的是确定CCR4在黑色素瘤脑转移中的功能意义。我们表明，CCR4是更高的表达脑转移黑色素瘤细胞比当地皮肤细胞从同一黑色素瘤。此外，我们发现，CCR4的表达是显着较高的配对的黑色素瘤转移的临床标本比原发性肿瘤的样品从相同的患者。值得注意的是，CCR4配体Ccl22和Ccl17的表达在脑转移的最早阶段上调，并且在黑素瘤细胞浸润到脑之前。在体外，CCL17诱导黑素瘤细胞的迁移和跨内皮迁移。在功能上，过表达CCR4的人黑色素瘤细胞比对照细胞具有更高的致瘤性，并产生更高的自发性脑微转移负荷。用小分子CCR4拮抗剂在体内阻断CCR4，可降低黑色素瘤细胞的致瘤性和微转移形成。总之，这些发现暗示CCR4是黑色素瘤脑转移的驱动因素。
We previously identified the chemokine receptor CCR4 as part of the molecular signature of melanoma brain metastasis. The aim of this study was to determine the functional significance of CCR4 in melanoma brain metastasis. We show that CCR4 is more highly expressed by brain metastasizing melanoma cells than by local cutaneous cells from the same melanoma. Moreover, we found that the expression of CCR4 is significantly higher in paired clinical specimens of melanoma metastases than in samples of primary tumors from the same patients. Notably, the expression of the CCR4 ligands, Ccl22 and Ccl17 is upregulated at the earliest stages of brain metastasis, and precedes the infiltration of melanoma cells to the brain. In-vitro, CCL17 induced migration and transendothelial migration of melanoma cells. Functionally, human melanoma cells over-expressing CCR4 were more tumorigenic and produced a higher load of spontaneous brain micrometastasis than control cells. Blocking CCR4 with a small molecule CCR4 antagonist in-vivo, reduced the tumorigenicity and micrometastasis formation of melanoma cells. Taken together, these findings implicate CCR4 as a driver of melanoma brain metastasis.