Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells.
Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells.
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DOI：
10.1158/0008-5472.can-08-4619
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发表时间：
2009-07-15
期刊：
影响因子：
11.2
通讯作者：
Biragyn A
中科院分区：
文献类型：
--
作者：
Olkhanud PB;Baatar D;Bodogai M;Hakim F;Gress R;Anderson RL;Deng J;Xu M;Briest S;Biragyn A
癌症转移是癌症发病和死亡的主要原因。我们需要更多地了解控制这一过程的机制。特别是，趋化因子受体在转移中的作用仍然存在争议。在这里，使用一个高转移性乳腺癌（4T1）模型，我们证明肺转移是只有一部分表达CCR4的肿瘤细胞的特征。此外，在乳腺垫中生长的原发肿瘤可以远程激活肺中TARC/CCL17和MDC/CCL22的表达。这些趋化因子通过CCR4吸引肿瘤细胞和免疫细胞。然而，CCR4介导的趋化性不足以产生转移，因为肺中的肿瘤细胞被NK细胞有效地清除。肺转移需要CCR4+ Tregs，它利用β -半乳糖苷结合蛋白直接杀死NK细胞。因此，取消这一过程的任何部分的策略应该通过激活效应细胞和防止肿瘤细胞迁移来改善结果。我们通过传递tarc融合毒素或消耗Tregs杀死CCR4+细胞并防止肺转移来证实这一预测。
Cancer metastasis is a leading cause of cancer morbidity and mortality. More needs to be learned about mechanisms that control this process. In particular, the role of chemokine receptors in metastasis remains controversial. Here, using a highly metastatic breast cancer (4T1) model, we demonstrate that lung metastasis is a feature of only a proportion of the tumor cells that express CCR4. Moreover, the primary tumor growing in mammary pads activates remotely the expression of TARC/CCL17 and MDC/CCL22 in the lungs. These chemokines acting through CCR4 attract both tumor and immune cells. However, CCR4 mediated chemotaxis was not sufficient to produce metastasis, as tumor cells in the lung were efficiently eliminated by NK cells. Lung metastasis required CCR4+ Tregs which directly killed NK cells utilizing beta-galactoside-binding protein. Thus, strategies that abrogate any part of this process should improve the outcome through activation of effector cells and prevention of tumor cell migration. We confirm this prediction by killing CCR4+ cells through delivery of TARC-fused toxins or depleting Tregs and preventing lung metastasis.