Niche-derived soluble DLK1 promotes glioma growth.
Niche-derived soluble DLK1 promotes glioma growth.
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DOI：
10.1016/j.neo.2020.10.005
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Pietras A
中科院分区：
文献类型：
--
作者：
Grassi ES;Jeannot P;Pantazopoulou V;Berg TJ;Pietras A
星形胶质细胞在缺氧或辐射后会分泌 DLK1。可溶性 DLK1 部分通过增加 HIF-2α 稳定性来促进神经胶质瘤的干性。高水平的可溶性 DLK1 与肿瘤的侵袭性和致死性相关。与侵袭性肿瘤生长相关的肿瘤细胞行为，例如增殖、治疗耐药和干细胞特征，部分受到来自肿瘤微环境的可溶性因子的调节。肿瘤相关星形胶质细胞是神经胶质瘤肿瘤微环境的主要组成部分，星形胶质细胞在维持干细胞微环境中正常神经干细胞方面发挥着积极作用，部分是通过分泌可溶性δ样非经典Notch配体1 (DLK1)。我们发现，当星形胶质细胞暴露于肿瘤微环境的应激（例如缺氧或电离辐射）时，可溶性 DLK1 的分泌增加。神经胶质瘤小鼠模型中的肿瘤相关星形胶质细胞在坏死周围和血管周围肿瘤区域表达 DLK1。暴露于重组 DLK1 的神经胶质瘤细胞显示出增殖增加、自我更新和集落形成能力增强以及干细胞标记基因水平增加。从机制上讲，DLK1介导的对神经胶质瘤细胞的作用涉及缺氧诱导因子2α的增加和延长的稳定性，并且抑制缺氧诱导因子2α活性消除了DLK1在缺氧中的作用。在基因工程小鼠神经胶质瘤模型中，可溶性 DLK1 的强制表达导致肿瘤生长更具侵袭性并缩短生存期。总之，我们的数据支持 DLK1 作为源自肿瘤微环境的神经胶质瘤侵袭性的可溶性介质。
Astrocytes secrete DLK1 after exposure to hypoxia or irradiation. Soluble DLK1 promotes stemness in glioma, in part by increasing HIF-2alpha stabilization. High levels of soluble DLK1 are associated with tumor aggressiveness and lethality. Tumor cell behaviors associated with aggressive tumor growth such as proliferation, therapeutic resistance, and stem cell characteristics are regulated in part by soluble factors derived from the tumor microenvironment. Tumor-associated astrocytes represent a major component of the glioma tumor microenvironment, and astrocytes have an active role in maintenance of normal neural stem cells in the stem cell niche, in part via secretion of soluble delta-like noncanonical Notch ligand 1 (DLK1). We found that astrocytes, when exposed to stresses of the tumor microenvironment such as hypoxia or ionizing radiation, increased secretion of soluble DLK1. Tumor-associated astrocytes in a glioma mouse model expressed DLK1 in perinecrotic and perivascular tumor areas. Glioma cells exposed to recombinant DLK1 displayed increased proliferation, enhanced self-renewal and colony formation abilities, and increased levels of stem cell marker genes. Mechanistically, DLK1-mediated effects on glioma cells involved increased and prolonged stabilization of hypoxia-inducible factor 2alpha, and inhibition of hypoxia-inducible factor 2alpha activity abolished effects of DLK1 in hypoxia. Forced expression of soluble DLK1 resulted in more aggressive tumor growth and shortened survival in a genetically engineered mouse model of glioma. Together, our data support DLK1 as a soluble mediator of glioma aggressiveness derived from the tumor microenvironment.
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