Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Beijing, 100005, China.
Brain Tumor Research Center, Beijing Neurosurgical Institute, Beijing Tiantan Hospital affiliated to Capital Medical University, Tiantan Xili 6, Dongcheng District, Beijing, 100050, China.
Stem Cell Res Ther. 2019 Apr 11;10(1):117. doi: 10.1186/s13287-019-1220-2.
Although adipocytes are the most abundant stromal cell component in breast cancer tissues, their interaction with breast cancer cells has been less investigated compared to cancer-associated fibroblasts or macrophages. Exosomes are a novel way of cell-cell communication and have been demonstrated to play an important role in various biological processes. However, to our knowledge, only a few studies have reported the effects of adipocyte exosomes on tumor development. Here, utilizing exosomes isolated from in vitro mesenchymal stromal/stem cell (MSC)-differentiated adipocytes, we systematically investigated this issue in a breast cancer model.
Exosomes were isolated from MSC-differentiated adipocytes and added to breast cancer cells MCF7. Cell proliferation was detected by MTS, and migration was analyzed by wound healing and transwell assay. An in vivo mouse xenograft model was used to evaluate MSC-differentiated adipocyte exosomes' contribution to tumor growth. Signaling pathway activation was evaluated by western blot and immunofluorescence staining.
We found MSC-differentiated adipocyte-derived exosomes are actively incorporated by breast cancer cell MCF7 and subsequently promote MCF7 proliferation and migration as well as protect MCF7 from serum derivation or chemotherapeutic drug-induced apoptosis in vitro. In the in vivo mouse xenograft model, depletion of exosomes reduces tumor-promoting effects of adipocytes. Transcriptomic analysis of MSC-differentiated adipocyte exosome-treated MCF7 identified several activated signaling pathways, among which we confirm the Hippo signaling pathway and found a blockade of this pathway leads to a reduced growth-promoting effect of adipocyte exosomes.
Taken together, our findings provide new insights into the role of adipocyte exosomes in the tumor microenvironment.
尽管脂肪细胞是乳腺癌组织中最丰富的基质细胞成分，但与癌相关成纤维细胞或巨噬细胞相比，它们与乳腺癌细胞的相互作用研究较少。外泌体是一种新型的细胞间通讯方式，已被证明在各种生物学过程中发挥重要作用。然而，据我们所知，只有少数研究报道了脂肪细胞外泌体对肿瘤发展的影响。在这里，我们利用体外间充质基质/干细胞 (MSC) 分化的脂肪细胞分离的外泌体，在乳腺癌模型中系统地研究了这个问题。
从 MSC 分化的脂肪细胞中分离出外泌体，并将其添加到乳腺癌细胞 MCF7 中。通过 MTS 检测细胞增殖，通过划痕愈合和 Transwell 分析检测细胞迁移。使用体内小鼠异种移植模型来评估 MSC 分化的脂肪细胞外泌体对肿瘤生长的贡献。通过 Western blot 和免疫荧光染色评估信号通路的激活。
我们发现 MSC 分化的脂肪细胞衍生的外泌体被乳腺癌细胞 MCF7 主动摄取，并随后促进 MCF7 的增殖和迁移，并在体外保护 MCF7 免受血清来源或化疗药物诱导的凋亡。在体内小鼠异种移植模型中，外泌体的耗竭减少了脂肪细胞的促瘤作用。对 MSC 分化的脂肪细胞外泌体处理的 MCF7 的转录组分析鉴定出几个激活的信号通路，其中我们证实了 Hippo 信号通路，并发现阻断该通路可降低脂肪细胞外泌体的促生长作用。
总之，我们的研究结果为脂肪细胞外泌体在肿瘤微环境中的作用提供了新的见解。
Zotero 插件
