Systemic neutralization of IL-17A significantly reduces breast cancer associated metastasis in arthritic mice by reducing CXCL12/SDF-1 expression in the metastatic niches.
Systemic neutralization of IL-17A significantly reduces breast cancer associated metastasis in arthritic mice by reducing CXCL12/SDF-1 expression in the metastatic niches.
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DOI：
10.1186/1471-2407-14-225
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发表时间：
2014-03-27
期刊：
影响因子：
3.8
通讯作者：
Mukherjee P
中科院分区：
文献类型：
--
作者：
Roy LD;Sahraei M;Schettini JL;Gruber HE;Besmer DM;Mukherjee P
IL-17A是一种促炎性细胞因子，通常与自身免疫性关节炎和其他促炎性疾病有关。最近，IL-17A已成为促进乳腺癌（BC）相关转移的关键因素。我们建立了具有免疫能力的关节炎小鼠模型，这些模型发生自发的bc相关骨和肺转移。利用这些模型，我们之前已经表明，IL-17A的中和导致转移的显著减少。然而，潜在的机制仍然未知。我们在这项研究中使用了两种先前发表的小鼠模型：1)在乳腺脂肪垫中注射转移性BC细胞系（4T1）的促关节炎小鼠模型（指定SKG），以及2)在自发性乳腺肿瘤中注射II型胶原诱导自身免疫性关节炎的PyV MT小鼠。用抗il - 17a中和抗体治疗小鼠，监测其转移，并评估与bc相关转移相关的促炎细胞因子和趋化因子。我们首先证实了我们之前的发现，即在两种模型中，体内中和IL-17A可显著减少骨和肺转移。接下来，我们报道用抗il17a抗体治疗显著降低了一种关键趋化因子CXCL12（也称为基质衍生因子-1 (SDF -1)）在治疗小鼠骨骼和肺部的表达。CXCL12是CXCR4的配体（在BC细胞上表达），它们之间的相互作用是转移的关键。有趣的是，肿瘤中CXCR4的水平在治疗过程中保持不变。因此，来自治疗小鼠骨骼和肺部的蛋白裂解物对BC细胞的趋化性明显低于来自未治疗小鼠的裂解物；在处理小鼠的裂解物中加入外源性SDF-1完全恢复了BC细胞的迁移。此外，治疗后肺和骨裂解液中IL-6和M-CSF等细胞因子显著降低。上述数据表明，在两种小鼠模型中，系统中和IL-17A可以通过降低转移小生境中SDF-1的表达来阻断CXCR4/SDF-1信号通路，并显著减少转移。在我们的模型中，IL-17A的中和通过降低IL-6和M-CSF的水平直接或间接地调节转移性小生境中SDF-1的表达。
IL-17A is a pro-inflammatory cytokine that is normally associated with autoimmune arthritis and other pro-inflammatory conditions. Recently, IL-17A has emerged as a critical factor in enhancing breast cancer (BC)-associated metastases. We generated immune competent arthritic mouse models that develop spontaneous BC-associated bone and lung metastasis. Using these models, we have previously shown that neutralization of IL-17A resulted in significant reduction in metastasis. However, the underlying mechanism/s remains unknown. We have utilized two previously published mouse models for this study: 1) the pro-arthritic mouse model (designated SKG) injected with metastatic BC cell line (4T1) in the mammary fat pad, and 2) the PyV MT mice that develop spontaneous mammary gland tumors injected with type II collagen to induce autoimmune arthritis. Mice were treated with anti-IL-17A neutralizing antibody and monitored for metastasis and assessed for pro-inflammatory cytokines and chemokines associated with BC-associated metastasis. We first corroborate our previous finding that in vivo neutralization of IL-17A significantly reduced metastasis to the bones and lungs in both models. Next, we report that treatment with anti-IL17A antibody significantly reduced the expression of a key chemokine, CXCL12 (also known as stromal derived factor-1 (SDF - 1)) in the bones and lungs of treated mice. CXCL12 is a ligand for CXCR4 (expressed on BC cells) and their interaction is known to be critical for metastasis. Interestingly, levels of CXCR4 in the tumor remained unchanged with treatment. Consequently, protein lysates derived from the bones and lungs of treated mice were significantly less chemotactic for the BC cells than lysates from untreated mice; and addition of exogenous SDF-1 to the lysates from treated mice completely restored BC cell migration. In addition, cytokines such as IL-6 and M-CSF were significantly reduced in the lung and bone lysates following treatment. The data presented suggests that systemic neutralization of IL-17A can block the CXCR4/SDF-1 signaling pathway by reducing the expression of SDF-1 in the metastatic niches and significantly reducing metastasis in both mouse models. In our model, neutralization of IL-17A regulates SDF-1 expression in the metastatic niches either directly or indirectly via reducing levels of IL-6 and M-CSF.
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影响因子：
3.8
作者：
Das Roy, Lopamudra;Ghosh, Sriparna;Mukherjee, Pinku
通讯作者：
Mukherjee, Pinku
影响因子：
4.4
作者：
D Basu, Gargi;Tinder, Teresa L.;Mukherjee, Pinku
通讯作者：
Mukherjee, Pinku
DOI：
10.1186/bcr2345
发表时间：
2009
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Das Roy L;Pathangey LB;Tinder TL;Schettini JL;Gruber HE;Mukherjee P
通讯作者：
Mukherjee P
DOI：
10.1186/bcr3412
发表时间：
2013-04-11
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Das Roy L;Curry JM;Sahraei M;Besmer DM;Kidiyoor A;Gruber HE;Mukherjee P
通讯作者：
Mukherjee P
影响因子：
5.5
作者：
Ji, Jianguang;Liu, Xiangdong;Sundquist, Jan
通讯作者：
Sundquist, Jan