Ly6G+ inflammatory cells enable the conversion of cancer cells to cancer stem cells in an irradiated glioblastoma model.,Cell Death and Differentiation

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Ly6G+ inflammatory cells enable the conversion of cancer cells to cancer stem cells in an irradiated glioblastoma model.
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2019-02-25 , DOI: 10.1038/s41418-019-0282-0
Hee-Young Jeon _{1,

2} , Seok Won Ham _{1,

2} , Jun-Kyum Kim _{1,

2} , Xiong Jin _{1,

2} , Seon Yong Lee ₁ , Yong Jae Shin _{3,

4} , Chang-Yong Choi _{1,

2} , Jason K Sa ₄ , Se Hoon Kim ₅ , Taehoon Chun _{1,

2} , Xun Jin _{6,

7} , Do-Hyun Nam _{3,

4,

8} , Hyunggee Kim _{1,

2,

9}

Affiliation

Most glioblastomas frequently recur at sites of radiotherapy, but it is unclear if changes in the tumor microenvironment due to radiotherapy influence glioblastoma recurrence. Here, we demonstrate that radiation-induced senescent glioblastoma cells exhibit a senescence-associated secretory phenotype that functions through NFκB signaling to influence changes in the tumor microenvironment, such as recruitment of Ly6G+ inflammatory cells and vessel formation. In particular, Ly6G+ cells promote conversion of glioblastoma cells to glioblastoma stem cells (GSCs) through the NOS2-NO-ID4 regulatory axis. Specific inhibition of NFκB signaling in irradiated glioma cells using the IκBα super repressor prevents changes in the tumor microenvironment and dedifferentiation of glioblastoma cells. Treatment with Ly6G-neutralizing antibodies also reduces the number of GSCs and prolongs survival in tumor-bearing mice after radiotherapy. Clinically, a positive correlation exists between Ly6G+ cells and the NOS2-NO-ID4 regulatory axis in patients diagnosed with recurrent glioblastoma. Together, our results illustrate important roles for Ly6G+ inflammatory cells recruited by radiation-induced SASP in cancer cell dedifferentiation and tumor recurrence.

中文翻译：

在辐射的胶质母细胞瘤模型中，Ly6G +炎症细胞使癌细胞能够转化为癌干细胞。

大多数胶质母细胞瘤经常在放疗部位复发，但是尚不清楚由于放疗引起的肿瘤微环境变化是否会影响胶质母细胞瘤的复发。在这里，我们证明了辐射诱导的衰老胶质母细胞瘤细胞表现出衰老相关的分泌表型，该表型通过NFκB信号传导来影响肿瘤微环境的变化，例如Ly6G +炎症细胞的募集和血管形成。尤其是，Ly6G +细胞通过NOS2-NO-ID4调控轴促进胶质母细胞瘤细胞向胶质母细胞瘤干细胞（GSC）的转化。使用IκBα超级阻遏剂特异性抑制照射的神经胶质瘤细胞中的NFκB信号传导，可防止肿瘤微环境的改变和胶质母细胞瘤细胞的去分化。Ly6G中和抗体的治疗还可以减少放疗后荷瘤小鼠中GSC的数量，并延长生存期。临床上，在诊断患有复发性胶质母细胞瘤的患者中，Ly6G +细胞与NOS2-NO-ID4调节轴之间存在正相关。在一起，我们的结果说明了辐射诱导的SASP募集的Ly6G +炎性细胞在癌细胞去分化和肿瘤复发中的重要作用。

更新日期：2019-02-25

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