Jagged1 promotes aromatase inhibitor resistance by modulating tumor-associated macrophage differentiation in breast cancer patients
Jagged1 promotes aromatase inhibitor resistance by modulating tumor-associated macrophage differentiation in breast cancer patients
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DOI：
10.1007/s10549-017-4394-2
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发表时间：
2017-11-01
影响因子：
3.8
通讯作者：
Zhang, Qingyuan
中科院分区：
文献类型：
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作者：
Liu, Hang;Wang, Jingxuan;Zhang, Qingyuan
内分泌抵抗限制了抗雌激素疗法的功效。Notch信号转导参与调节肿瘤相关巨噬细胞（TAM）分化，并在内分泌抵抗性乳腺癌细胞中上调。在此，我们分析了Jagged 1在TAM极化调节中的作用，以研究Jagged 1-Notch通路是否通过上调TAM浸润来促进芳香化酶抑制剂（aromatase inhibitor，AI）抗性的获得。在203例接受AI治疗的ER阳性绝经后患者的肿瘤样本中，采用免疫组化染色法进行评价，并与临床病理参数和生存率进行比较。在MCF-7和长期内分泌耗竭（LTED）细胞系中分析Jagged 1蛋白和mRNA水平。用流式细胞仪检测巨噬细胞与MCF-7或LTED细胞共培养后的表型。进行细胞迁移测定以评估癌细胞的迁移率。采用Notch γ分泌酶抑制剂（GSI）RO 4929097研究Notch信号通路的调节是否影响M2极化。在肿瘤标本中，Jagged 1的表达与肿瘤体积大、组织学分级高、淋巴管浸润和Ki 67高表达相关。Jagged 1表达也与无病生存期和总生存期降低相关，与原发肿瘤组织中间质M2 TAM浸润密度呈正相关。在AI耐药患者中，M2 TAM在转移性病变中的浸润比原发性肿瘤中更致密。与MCF-7细胞相比，在LTED细胞中也发现了更高的Jagged 1蛋白和mRNA水平，LTED细胞模拟了患者的AI耐药状况。与LTED细胞共培养的巨噬细胞表达更高水平的M2标志物和IL-10。GSI预处理后巨噬细胞中M2 TAM比例降低，Jagged 1-Notch通路在AI耐药乳腺癌细胞中表达增加，导致巨噬细胞向M2 TAM分化，从而促进AI耐药的获得。
Endocrine resistance limits the efficacy of anti-estrogen therapies. Notch signaling is involved in modulating tumor-associated macrophage (TAM) differentiation and is upregulated in endocrine-resistant breast cancer cells. Here, we analyzed the role of Jagged1 in the regulation of TAM polarization to investigate whether the Jagged1-Notch pathway promotes the acquisition of aromatase inhibitor (AI) resistance by upregulating TAM infiltration.The Jagged1 expression levels and M2 TAM infiltration density, in 203 tumor samples from ER-positive postmenopausal patients, who received AI treatment, were evaluated by immunohistochemical staining and the results were compared with clincopathological parameters and survival. The Jagged1 protein and mRNA levels were analyzed in MCF-7 and long-term endocrine-depleted (LTED) cell lines. The phenotypes of macrophage after macrophages were co-cultured with either MCF-7 or LTED cells, were evaluated using flow cytometry. Cell migration assay was performed to evaluate the mobility of cancer cells. Notch gama secretase inhibitor (GSI) RO4929097 was employed to investigate whether modulation of Notch signaling affects M2 polarization.In the tumor samples, Jagged1 expression was found to be associated with a large tumor size, high histological grade, lymphatic invasion, and high Ki67 expression. Jagged1 expression was also correlated with reduced disease-free and overall survival and was positively associated with the stromal M2 TAM infiltration density in primary tumor tissues. In AI-resistance patients, M2 TAM infiltration was denser in metastatic lesions than in primary tumors. Higher Jagged1 protein and mRNA levels were also found in LTED cells, which model AI-resistant conditions in patients, compared with MCF-7 cells. Macrophages co-cultured with LTED cells expressed higher levels of M2 marker and IL-10. M2 TAM proportion was reduced when macrophages were pre-treated with GSI before co-culture.The Jagged1-Notch pathway showed elevated expression in AI-resistant breast cancer cells, resulting in macrophage differentiation towards M2 TAMs and there contributing to the acquisition of AI resistance.