RKIP regulates CCL5 expression to inhibit breast cancer invasion and metastasis by controlling macrophage infiltration.
RKIP regulates CCL5 expression to inhibit breast cancer invasion and metastasis by controlling macrophage infiltration.
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DOI：
10.18632/oncotarget.5176
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发表时间：
2015-11-17
期刊：
影响因子：
--
通讯作者：
Yeung KC
中科院分区：
文献类型：
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作者：
Datar I;Qiu X;Ma HZ;Yeung M;Aras S;de la Serna I;Al-Mulla F;Thiery JP;Trumbly R;Fan X;Cui H;Yeung KC
越来越多的证据表明，肿瘤微环境中巨噬细胞的存在通过分泌血管生成和生长因子增加了癌细胞的侵袭性和肿瘤促进特征。RKIP是一种已知的转移抑制因子，并干扰转移的几个步骤。然而，其作为广泛的转移抑制剂的功能的机制基础仍然知之甚少。在这里，我们建立了一个新的途径RKIP调节转移抑制通过负调节RANTES/CCL5，从而限制肿瘤巨噬细胞浸润和抑制血管生成。使用功能丧失和获得的方法相结合，我们表明，RKIP通过抑制CC趋化因子CCL5的表达在体外阻碍乳腺癌细胞的侵袭。我们还表明，RKIP和CCL5的表达水平在临床人乳腺癌样品中呈负相关。使用小鼠同种异体乳腺癌移植模型，我们强调RKIP的异位表达显著降低肿瘤血管，巨噬细胞浸润和肺转移。从机制上讲，我们证明了CCL5表达的抑制是由RKIP表达引起的观察到的效应的原因。总之，我们的研究结果强调了RKIP作为肿瘤微环境重要负调节因子的重要性。
Accumulating evidence suggests that presence of macrophages in the tumor microenvironment add to the invasive and tumor-promoting hallmarks of cancer cells by secreting angiogenic and growth factors. RKIP is a known metastasis suppressor and interferes with several steps of metastasis. However, the mechanistic underpinnings of its function as a broad metastasis suppressor remain poorly understood. Here, we establish a novel pathway for RKIP regulation of metastasis inhibition through the negative regulation of RANTES/CCL5 thereby limiting tumor macrophage infiltration and inhibition of angiogenesis. Using a combination of loss- and gain-of-function approaches, we show that RKIP hinders breast cancer cell invasion by inhibiting expression of the CC chemokine CCL5 in vitro. We also show that the expression levels of RKIP and CCL5 are inversely correlated among clinical human breast cancer samples. Using a mouse allograft breast cancer transplantation model, we highlight that ectopic expression of RKIP significantly decreases tumor vasculature, macrophage infiltration and lung metastases. Mechanistically, we demonstrate that the inhibition of the CCL5 expression is the cause of the observed effects resulting from RKIP expression. Taken together, our results underscore the significance of RKIP as important negative regulator of tumor microenvironment.