Suppression of HMGB1 Released in the Glioblastoma Tumor Microenvironment Reduces Tumoral Edema
Suppression of HMGB1 Released in the Glioblastoma Tumor Microenvironment Reduces Tumoral Edema
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DOI：
10.1016/j.omto.2018.11.005
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发表时间：
2019-03-29
影响因子：
5.7
通讯作者：
Kaur, Balveen
中科院分区：
文献类型：
--
作者：
Hong, Bangxing;Muili, Kamaldeen;Kaur, Balveen
HMGB1是一种普遍表达的细胞内蛋白，它结合DNA和转录因子，调节染色体的结构和功能。在细胞死亡或应激的情况下，细胞主动或被动地将其释放到细胞外环境中，在细胞外环境中，它以损伤相关分子模式(DAMP)的形式发挥作用，协调促炎细胞因子的释放和炎症。我们的结果表明，HMGB1在体外和体内均能在溶瘤HSV(OHSV)感染后的肿瘤微环境中分泌。用HMGB1封闭抗体在体外和荷瘤小鼠体内评价分泌的HMGB1对肿瘤生长和对溶瘤病毒治疗的反应的影响。IVIS和MRI成像被用来实时观察病毒在小鼠体内的扩散、肿瘤生长和水肿的变化。我们的数据显示，在肿瘤微环境中释放的HMGB1导致血管渗漏和水肿增加。此外，HMGB1阻断抗体挽救了OHSV治疗的颅内胶质瘤荷瘤小鼠的血管渗漏并提高了存活率。
HMGB1 is a ubiquitously expressed intracellular protein that binds DNA and transcription factors and regulates chromosomal structure and function. Under conditions of cell death or stress, it is actively or passively released by cells into the extracellular environment, where it functions as damage-associated molecular pattern (DAMP) that orchestrates pro-inflammatory cytokine release and inflammation. Our results demonstrate that HMGB1 is secreted in the tumor microenvironment after oncolytic HSV (oHSV) infection in vitro and in vivo. The impact of secreted HMGB1 on tumor growth and response to oncolytic viral therapy was evaluated by using HMGB1-blocking antibodies in vitro and in mice bearing intracranial tumors. IVIS and MRI imaging was utilized to visualize in real time virus spread, tumor growth, and changes in edema in mice. Our data showed that HMGB1 released in tumor microenvironment orchestrated increased vascular leakiness and edema. Further HMGB1 blocking antibodies rescued vascular leakiness and enhanced survival of intracranial glioma-bearing mice treated with oHSV.