MDSCs mediate angiogenesis and predispose canine mammary tumor cells for metastasis via IL-28/IL-28RA (IFN-λ) signaling.
MDSCs mediate angiogenesis and predispose canine mammary tumor cells for metastasis via IL-28/IL-28RA (IFN-λ) signaling.
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DOI：
10.1371/journal.pone.0103249
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Król M
中科院分区：
文献类型：
--
作者：
Mucha J;Majchrzak K;Taciak B;Hellmén E;Król M
骨髓源性抑制细胞（MDSCs）通过诱导血管生成以stat3依赖的方式在免疫抑制和肿瘤发展中起作用。对MDSC生物学的了解主要局限于小鼠研究，需要更多的使用自发性肿瘤模型的临床研究。在这里，我们进行了体外实验和从犬患者身上获得的临床数据分析。利用微阵列技术，我们检测了犬乳腺癌细胞与MDSCs共培养后基因表达的变化。此外，通过实时rt-PCR、Western blot、免疫组化、siRNA、血管生成试验和迁移/侵袭试验，我们研究了最重要的信号通路的作用。在患有乳腺癌的狗中，循环MDSCs的数量随着肿瘤的临床分期而增加。微阵列分析显示，MDSCs在体外肿瘤细胞中显著改变了分子通路。特别重要的是检测到IL-28/IL-28RA （IFN-λ）信号的激活增加。IL-28在III/IV期乳腺肿瘤犬中表达最高。MDSCs分泌的IL-28刺激肿瘤细胞中的STAT3，导致血管生成因子的表达增加，进而诱导内皮细胞血管生成、上皮间质转化（epithelial-mesenchymal transition， EMT）和肿瘤细胞的体外迁移。IL-28RA的表达降低了血管生成、肿瘤细胞的侵袭和迁移。我们首次发现MDSCs分泌IL-28 (IFN-λ)，促进血管生成、EMT、肿瘤细胞的侵袭和迁移。因此，IL-28可能成为进一步治疗的有趣靶点。此外，犬和人类患者在不同肿瘤临床阶段循环MDSC水平的相似性表明，犬是针对MDSC的药物临床试验的良好模型。
Myeloid-derived suppressor cells (MDSCs) function in immunosuppression and tumor development by induction of angiogenesis in a STAT3-dependent manner. Knowledge of MDSC biology is mainly limited to mice studies, and more clinical investigations using spontaneous tumor models are required. Here we performed in vitro experiments and clinical data analysis obtained from canine patients. Using microarrays we examined changes in gene expression in canine mammary cancer cells due to their co-culture with MDSCs. Further, using Real-time rt-PCR, Western blot, IHC, siRNA, angiogenesis assay and migration/invasion tests we examined a role of the most important signaling pathway. In dogs with mammary cancer, the number of circulating MDSCs increases with tumor clinical stage. Microarray analysis revealed that MDSCs had significantly altered molecular pathways in tumor cells in vitro. Particularly important was the detected increased activation of IL-28/IL-28RA (IFN-λ) signaling. The highest expression of IL-28 was observed in stage III/IV mammary tumor-bearing dogs. IL-28 secreted by MDSCs stimulates STAT3 in tumor cells, which results in increased expression of angiogenic factors and subsequent induction of angiogenesis by endothelial cells, epithelial-mesenchymal transition (EMT) and increased migration of tumor cells in vitro. Knockdown of IL-28RA decreased angiogenesis, tumor cell invasion and migration. We showed for the first time that MDSCs secrete IL-28 (IFN-λ), which promotes angiogenesis, EMT, invasion and migration of tumor cells. Thus, IL-28 may constitute an interesting target for further therapies. Moreover, the similarity in circulating MDSC levels at various tumor clinical stages between canine and human patients indicates canines as a good model for clinical trials of drugs targeting MDSCs.
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