Glioma stem cell (GSC)-derived autoschizis-like products confer GSC niche properties involving M1-like tumor-associated macrophages
Glioma stem cell (GSC)-derived autoschizis-like products confer GSC niche properties involving M1-like tumor-associated macrophages
复制标题
胶质瘤干细胞 (GSC) 衍生的自分裂样产物赋予 GSC 利基特性，涉及 M1 样肿瘤相关巨噬细胞
DOI：
10.1002/stem.3193
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发表时间：
2020
期刊：
影响因子：
5.2
通讯作者：
Hide T and Taga T
中科院分区：
文献类型：
--
作者：
Tabu K;Liu W;Kosaku A;Terashima K;Murota Y;Aimaitijiang A;Nobuhisa I;Hide T and Taga T
自发性坏死是胶质母细胞瘤（GBM）（最恶性的胶质瘤）的一个定义特征。尽管坏死与不良预后密切相关，但目前尚不清楚坏死是否是神经胶质瘤进展的可能原因或仅仅是其结果。在这里，我们分离了胶质瘤细胞自发产生的坏死产物的特定部分，在形态学和生物化学上定义为类自裂产物（ALP）。当给予粒细胞巨噬细胞集落刺激因子（GM-CSF）引发的骨髓源性巨噬细胞/树突状细胞（Mφ/DC）时，发现ALP被表达肿瘤相关巨噬细胞（TAM）标记物CD204的Mφ特异性吞噬。来自神经胶质瘤干细胞 (GSC) 的 ALP 对 TAM 发育的活性比来自非 GSC 的 ALP 更高。值得注意的是，编码 IL-12/23 共同亚基的 Il12b 基因的表达在 ALP 诱导的 Mφ 中上调。此外，IL-12 蛋白明显增强了 GBM 患者来源的细胞的球体形成活性，尽管有趣的是 IL-12 通常被认为是抗肿瘤 M1-Mφ 标记物。最后，对原发性和复发性 GBM 的癌症基因组图谱 (TCGA) 转录组数据进行计算机分析表明，这些 IL-12 家族基因的较高表达与 M1 型 TAM 的更多浸润密切相关，并与复发性 GBM 的较差预后密切相关。我们的研究结果强调了坏死在 GSC 驱动的自利利基构建和神经胶质瘤进展中的作用，为开发针对神经胶质瘤的新治疗策略提供了重要线索。 意义陈述 尽管与不良预后密切相关，但目前尚不清楚坏死是否是神经胶质瘤进展的可能原因或仅仅是结果。在这里，一部分被称为自裂样产物的神经胶质瘤干细胞 (GSC) 衍生的坏死颗粒被确定为 GSC 支持的 M1 型肿瘤相关巨噬细胞发育的关键介质。因此，这项研究表明，神经胶质瘤坏死并不是无意义的死亡，而是一种对肿瘤有益的事件，为 GSC 驱动的生态位发育和神经胶质瘤进展的机制提供了新的见解。
Spontaneous necrosis is a defining feature of glioblastomas (GBMs), the most malignant glioma. Despite its strong correlations with poor prognosis, it remains unclear whether necrosis could be a possible cause or mere consequence of glioma progression. Here we isolated a particular fraction of necrotic products spontaneously arising from glioma cells, morphologically and biochemically defined as autoschizis-like products (ALPs). When administered to granulocyte macrophage colony-stimulating factor (GM-CSF)-primed bone marrow-derived macrophage/dendritic cells (Mφ/DCs), ALPs were found to be specifically engulfed by Mφs expressing a tumor-associated macrophage (TAM) marker CD204. ALPs from glioma stem cells (GSCs) had higher activity for the TAM development than those from non-GSCs. Of note, expression of theIl12bgene encoding a common subunit of IL-12/23 was upregulated in ALPs-educated Mφs. Furthermore, IL-12 protein evidently enhanced the sphere-forming activity of GBM patient-derived cells, although interestingly IL-12 is generally recognized as an antitumoral M1-Mφ marker. Finally, in silico analysis of The Cancer Genome Atlas (TCGA) transcriptome data of primary and recurrent GBMs revealed that higher expression of these IL-12 family genes was well correlated with more infiltration of M1-type TAMs and closely associated with poorer prognosis in recurrent GBMs. Our results highlight a role of necrosis in GSC-driven self-beneficial niche construction and glioma progression, providing important clues for developing new therapeutic strategies against gliomas.Significance statementDespite strong correlations with poor prognosis, it remains unclear whether necrosis is a possible cause or mere consequence of glioma progression. Here, a fraction of glioma stem cell (GSC)-derived necrotic particles designated as autoschizis-like products was identified as a key mediator of the development of GSC-supportive M1-type tumor-associated macrophages. This study thus demonstrates that glioma necrosis is not a meaningless death but is a tumor-beneficial event, providing new insights into the mechanisms underlying GSC-driven niche development and glioma progression.