Department of Biology, University of North Carolina at Charlotte, 9201 University City Blvd, Charlotte, NC 28223, USA.
BMC Cancer. 2014 Mar 27;14:225. doi: 10.1186/1471-2407-14-225.
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.
IL-17A 是一种促炎细胞因子，通常与自身免疫性关节炎和其他促炎疾病有关。最近，IL-17A 已成为增强乳腺癌（BC）相关转移的关键因素。我们生成了具有自发 BC 相关骨和肺转移的免疫功能正常的关节炎小鼠模型。使用这些模型，我们之前已经表明，中和 IL-17A 可导致转移明显减少。然而，潜在的机制/仍然未知。
我们已经利用了两个先前发表的小鼠模型来进行这项研究：1）用转移性 BC 细胞系（4T1）注射到乳腺脂肪垫中的促关节炎小鼠模型（命名为 SKG），和 2）自发发生乳腺肿瘤的 PyV MT 小鼠，注射 II 型胶原以诱导自身免疫性关节炎。用抗 IL-17A 中和抗体治疗小鼠，并监测转移情况，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 可显著减少向骨骼和肺部的转移。接下来，我们报告说，用抗 IL17A 抗体治疗可显著降低治疗小鼠骨骼和肺部中关键趋化因子 CXCL12（也称为基质衍生因子-1（SDF-1））的表达。CXCL12 是 CXCR4（在 BC 细胞上表达）的配体，它们的相互作用对于转移至关重要。有趣的是，治疗后肿瘤中的 CXCR4 水平保持不变。因此，来自治疗小鼠的骨骼和肺部的蛋白裂解物对 BC 细胞的趋化性明显低于未治疗小鼠的裂解物；并且向治疗小鼠的裂解物中添加外源性 SDF-1 完全恢复了 BC 细胞的迁移。此外，治疗后肺部和骨骼裂解物中的细胞因子（如 IL-6 和 M-CSF）显着减少。所提出的数据表明，通过降低转移灶中 SDF-1 的表达，全身性中和 IL-17A 可以阻断 CXCR4/SDF-1 信号通路，并显著减少两种小鼠模型中的转移。
在我们的模型中，中和 IL-17A 通过降低 IL-6 和 M-CSF 的水平，直接或间接调节转移灶中 SDF-1 的表达。
