miRNA dynamics in tumor-infiltrating myeloid cells modulating tumor progression in pancreatic cancer
miRNA dynamics in tumor-infiltrating myeloid cells modulating tumor progression in pancreatic cancer
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DOI：
10.1080/2162402x.2016.1160181
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发表时间：
2016-01-01
期刊：
影响因子：
7.2
通讯作者：
Michl, Patrick
中科院分区：
文献类型：
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作者：
Muehlberg, Leonie;Kuehnemuth, Benjamin;Michl, Patrick
髓系细胞包括肿瘤相关巨噬细胞()和髓系来源的抑制细胞(MDSC)，在胰腺癌等实体瘤中是重要的肿瘤进展介质。浸润性髓系细胞不仅在侵袭性肿瘤中被发现，而且在早期侵袭性胰腺上皮内前体病变(Panin)中也被发现。髓系细胞在癌变过程中的功能动力学在很大程度上是未知的。我们的目的是系统地阐明胰腺癌遗传小鼠模型肿瘤发生和发展过程中浸润性髓系细胞的表型和转录变化。使用在致癌过程中不同时间点从遗传小鼠模型中分离的小鼠胰腺髓系细胞，我们利用RT-PCR和FACS检测了已建立的巨噬细胞极化标记以及以miRNA图谱为重点的转录变化。在癌变过程中分离的髓系细胞在癌变过程中M1和M2极化的已建立的标志物同时增加，这表明在癌变过程中髓系细胞的表型变化不符合已建立的M1/M2分类。MiRNA图谱显示，几个已经存在于侵袭前Panin病变的髓系细胞中的miRNA具有明显的调节作用。其中，miRNA-21在Panin皮损和浸润性癌周围的髓系细胞中显着增加。在功能上，miRNA-21-5p和-3p分别改变免疫调节细胞因子CXCL-10和CCL-3的表达。我们的数据表明，在癌变过程中，miRNAs在浸润性髓系细胞中受到动态调节，并通过促进免疫抑制的肿瘤促进微环境来调节其功能表型。
Myeloid cells including tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) are known as important mediators of tumor progression in solid tumors such as pancreatic cancer. Infiltrating myeloid cells have been identified not only in invasive tumors, but also in early pre-invasive pancreatic intraepithelial precursor lesions (PanIN). The functional dynamics of myeloid cells during carcinogenesis is largely unknown. We aimed to systematically elucidate phenotypic and transcriptional changes in infiltrating myeloid cells during carcinogenesis and tumor progression in a genetic mouse model of pancreatic cancer. Using murine pancreatic myeloid cells isolated from the genetic mouse model at different time points during carcinogenesis, we examined both established markers of macrophage polarization using RT-PCR and FACS as well as transcriptional changes focusing on miRNA profiling. Myeloid cells isolated during carcinogenesis showed a simultaneous increase of established markers of M1 and M2 polarization during carcinogenesis, indicating that phenotypic changes of myeloid cells during carcinogenesis do not follow the established M1/M2 classification. MiRNA profiling revealed distinct regulations of several miRNAs already present in myeloid cells infiltrating pre-invasive PanIN lesions. Among them miRNA-21 was significantly increased in myeloid cells surrounding both PanIN lesions and invasive cancers. Functionally, miRNA-21-5p and -3p altered expression of the immune-modulating cytokines CXCL-10 and CCL-3 respectively. Our data indicate that miRNAs are dynamically regulated in infiltrating myeloid cells during carcinogenesis and mediate their functional phenotype by facilitating an immune-suppressive tumor-promoting micro-milieu.