胶质母细胞瘤细胞与间质样干细胞之间的串扰通过 C5a/p38/ZEB1 轴促进胶质母细胞瘤的侵袭性。
Crosstalk between GBM cells and mesenchymal stemlike cells promotes the invasiveness of GBM through the C5a/p38/ZEB1 axis.
机构信息
Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.
Memorial Sloan Kettering, Cancer Center, New York, New York, USA.
出版信息
Neuro Oncol. 2020 Oct 14;22(10):1452-1462. doi: 10.1093/neuonc/noaa064.
BACKGROUND
Mesenchymal stemlike cells (MSLCs) have been detected in many types of cancer including brain tumors and have received attention as stromal cells in the tumor microenvironment. However, the cellular mechanisms underlying their participation in cancer progression remain largely unexplored. The aim of this study was to determine whether MSLCs have a tumorigenic role in brain tumors.
METHODS
To figure out molecular and cellular mechanisms in glioma invasion, we have cultured glioma with MSLCs in a co-culture system.
RESULTS
Here, we show that MSLCs in human glioblastoma (GBM) secrete complement component C5a, which is known for its role as a complement factor. MSLC-secreted C5a increases expression of zinc finger E-box-binding homeobox 1 (ZEB1) via activation of p38 mitogen-activated protein kinase (MAPK) in GBM cells, thereby enhancing the invasion of GBM cells into parenchymal brain tissue.
CONCLUSION
Our results reveal a mechanism by which MSLCs undergo crosstalk with GBM cells through the C5a/p38 MAPK/ZEB1 signaling loop and act as a booster in GBM progression.
KEY POINTS
- MSLCs activate p38 MAPK-ZEB1 signaling in GBM cells through C5a in a paracrine manner, thereby boosting the invasiveness of GBM cells in the tumor microenvironment.2. Neutralizing of C5a could be a potential therapeutic target for GBM by inhibition of mesenchymal phenotype.
背景
间充质干细胞样细胞（MSLCs）已在包括脑肿瘤在内的多种癌症中被检测到，并作为肿瘤微环境中的基质细胞受到关注。然而，它们参与癌症进展的细胞机制在很大程度上仍未得到探索。本研究旨在确定 MSLCs 在脑肿瘤中是否具有致瘤作用。
方法
为了确定胶质瘤侵袭的分子和细胞机制，我们在共培养系统中培养了含有 MSLCs 的胶质瘤。
结果
在这里，我们表明人脑胶质母细胞瘤（GBM）中的 MSLCs 分泌补体成分 C5a，C5a 因其作为补体因子的作用而闻名。MSLC 分泌的 C5a 通过激活 GBM 细胞中的 p38 丝裂原活化蛋白激酶（MAPK）增加锌指 E 盒结合同源盒 1（ZEB1）的表达，从而增强 GBM 细胞向实质脑组织的侵袭。
结论
我们的结果揭示了 MSLCs 通过 C5a/p38 MAPK/ZEB1 信号通路与 GBM 细胞进行串扰的机制，并在 GBM 进展中充当助推器。
要点
- MSLCs 通过旁分泌方式通过 C5a 激活 GBM 细胞中的 p38 MAPK-ZEB1 信号通路，从而增强肿瘤微环境中 GBM 细胞的侵袭性。2. 抑制 C5a 可能是抑制间充质表型的 GBM 的潜在治疗靶点。
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