Simultaneous blockade of IL-6 and CCL5 signaling for synergistic inhibition of triple-negative breast cancer growth and metastasis.
Simultaneous blockade of IL-6 and CCL5 signaling for synergistic inhibition of triple-negative breast cancer growth and metastasis.
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DOI：
10.1186/s13058-018-0981-3
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发表时间：
2018-06-14
期刊：
影响因子：
--
通讯作者：
Popel AS
中科院分区：
文献类型：
--
作者：
Jin K;Pandey NB;Popel AS
转移性三阴性乳腺癌(TNBC)是一种异质性、不治之症。为了寻找有效治疗TNBC的分子靶点，已进行了大量研究，但化疗仍是TNBC患者的主要选择。我们以前已经提出了白介素6(IL-6)和趋化因子(C-C基序)配体5(CCL5)在TNBC肿瘤生长和转移中的重要作用的证据。这些实验强调了癌细胞和间质淋巴管内皮细胞(LECs)之间的串扰在肿瘤生长和转移中的重要性。我们检测了与LECs共培养的MDA-MB-231-LN、SUM149和SUM159细胞在马拉韦罗(CCR5抑制剂)和tocilizumab(抗IL-6受体抗体)作用下的存活率和迁移能力。为了评价这两种药物联合应用对裸鼠模型的抗肿瘤作用，将MDA-MB-231-LN细胞接种于裸鼠乳房脂肪垫内，分别给予马拉韦罗(每天8 mg/kg)和cMR16-1(鼠抗IL-6R抗体替代物，10 mg/kg，ip，每周3次)，连续5周，观察其对肿瘤生长和胸部转移的影响。在本研究中，我们使用马拉韦罗和tocilizumab来证实IL-6和CCL5信号通路是促进TNBC细胞增殖和迁移的关键途径。此外，在异种移植小鼠模型中，我们发现抗IL6R抗体的小鼠版本cMR16-1显著抑制了肿瘤的生长。与单独用药相比，马拉韦罗和cMR16-1联合应用可显著抑制TNBC肿瘤的生长。值得注意的是，马拉韦罗和cMR16-1联合应用可减少胸部转移。综上所述，这些发现表明，促进TNBC和淋巴管之间的串扰的IL-6和CCL5信号是TNBC肿瘤生长和转移的关键增强剂。此外，这些结果表明，抑制这些通路的药物组合可能是治疗TNBC患者的一种有前途的治疗方法。本文的在线版本(10.1186/s130580180981-3)包含补充材料，可供授权用户使用。
Metastatic triple-negative breast cancer (TNBC) is a heterogeneous and incurable disease. Numerous studies have been conducted to seek molecular targets to treat TNBC effectively, but chemotherapy is still the main choice for patients with TNBC. We have previously presented evidence of the important roles of interleukin-6 (IL-6) and chemokine (C-C motif) ligand 5 (CCL5) in TNBC tumor growth and metastasis. These experiments highlighted the importance of the crosstalk between cancer cells and stromal lymphatic endothelial cells (LECs) in tumor growth and metastasis. We examined the viability and migration of MDA-MB-231-LN, SUM149, and SUM159 cells co-cultured with LECs when treated with maraviroc (CCR5 inhibitor) and tocilizumab (anti-IL-6 receptor antibody). To assess the anti-tumor effects of the combination of these two drugs in an athymic nude mouse model, MDA-MB-231-LN cells were implanted in the mammary fat pad and maraviroc (8 mg/kg, orally daily) and cMR16-1 (murine surrogate of the anti-IL-6R antibody, 10 mg/kg, IP, 3 days a week) were administrated for 5 weeks and effects on tumor growth and thoracic metastasis were measured. In this study, we used maraviroc and tocilizumab to confirm that IL-6 and CCL5 signaling are key pathways promoting TNBC cell proliferation and migration. Further, in a xenograft mouse model, we showed that tumor growth was dramatically inhibited by cMR16-1, the mouse version of the anti-IL6R antibody. The combination of maraviroc and cMR16-1 caused significant reduction of TNBC tumor growth compared to the single agents. Significantly, the combination of maraviroc and cMR16-1 abrogated thoracic metastasis. Taken together, these findings show that IL-6 and CCL5 signaling, which promote crosstalk between TNBC and lymphatic vessels, are key enhancers of TNBC tumor growth and metastasis. Furthermore, these results demonstrate that a drug combination inhibiting these pathways may be a promising therapy for TNBC patients. The online version of this article (10.1186/s13058-018-0981-3) contains supplementary material, which is available to authorized users.
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影响因子：
11.2
作者：
Hartman ZC;Poage GM;den Hollander P;Tsimelzon A;Hill J;Panupinthu N;Zhang Y;Mazumdar A;Hilsenbeck SG;Mills GB;Brown PH
通讯作者：
Brown PH
影响因子：
4.3
作者：
Li, Zhen-Jun;Ying, Xiao-Jiang;Zhou, Shu-Zhen
通讯作者：
Zhou, Shu-Zhen
DOI：
10.1016/j.biocel.2011.08.020
发表时间：
2011-12-01
影响因子：
4
作者：
Lee, Esak;Rosca, Elena V.;Popel, Aleksander S.
通讯作者：
Popel, Aleksander S.
影响因子：
4.8
作者：
Stacker, SA;Stenvers, K;Achen, MG
通讯作者：
Achen, MG
影响因子：
--
作者：
Steinskog ES;Sagstad SJ;Wagner M;Karlsen TV;Yang N;Markhus CE;Yndestad S;Wiig H;Eikesdal HP
通讯作者：
Eikesdal HP