Elimination of Radiation-Induced Senescence in the Brain Tumor Microenvironment Attenuates Glioblastoma Recurrence.
Elimination of Radiation-Induced Senescence in the Brain Tumor Microenvironment Attenuates Glioblastoma Recurrence.
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消除脑肿瘤微环境中辐射诱导的衰老会减轻胶质母细胞瘤的复发。
DOI：
10.1158/0008-5472.can-21-0752
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发表时间：
2021-12-01
期刊：
影响因子：
11.2
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中科院分区：
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作者：
胶质母细胞瘤（GBM）通常用电离辐射（IR）治疗，但不可避免地复发并产生耐药性。在治疗过程中，肿瘤周围的组织也受到照射。IR有效地诱导衰老，并且衰老的基质细胞可以通过分泌产生衰老相关分泌表型（SASP）的因子来促进邻近肿瘤细胞的生长。在这里，我们进行了转录组学和致瘤性分析，在照射小鼠脑细胞，以阐明如何辐射诱导衰老的非肿瘤性脑细胞促进肿瘤生长。颅照射后，大脑发生了广泛的衰老，星形胶质细胞群体特别容易受到影响。照射的大脑显示出改变的转录组学特征，其特征在于CDKN 1A（p21）（衰老的关键执行者）和几种SASP因子（包括受体酪氨酸激酶（RTK）Met的配体HGF）的上调。小鼠脑的预照射增加了原位植入的胶质瘤细胞的Met驱动的生长和侵袭性。重要的是，照射的p21−/−小鼠大脑没有表现出衰老，因此未能促进肿瘤生长。衰老星形胶质细胞分泌HGF激活胶质瘤细胞中的Met并促进其体外迁移和侵袭，这可以被HGF中和抗体或Met抑制剂克唑替尼阻断。克唑替尼还减缓了植入预辐照大脑中的胶质瘤细胞的生长。用衰老清除药物ABT-263（navitoclax）治疗选择性地杀死体内衰老的星形胶质细胞，显著减弱植入预辐照大脑中的胶质瘤细胞的生长。这些结果表明，照射后的肿瘤微环境中的SASP因子通过RTK激活驱动GBM生长，强调了辅助衰老清除疗法预防放疗后GBM复发的潜在效用。
Glioblastomas (GBM) are routinely treated with ionizing radiation (IR) but inevitably recur and develop therapy resistance. During treatment, the tissue surrounding tumors is also irradiated. IR potently induces senescence, and senescent stromal cells can promote the growth of neighboring tumor cells by secreting factors that create a senescence-associated secretory phenotype (SASP). Here, we carried out transcriptomic and tumorigenicity analyses in irradiated mouse brains to elucidate how radiation-induced senescence of non-neoplastic brain cells promotes tumor growth. Following cranial irradiation, widespread senescence in the brain occurred, with the astrocytic population being particularly susceptible. Irradiated brains showed an altered transcriptomic profile characterized by upregulation of CDKN1A (p21), a key enforcer of senescence, and several SASP factors including HGF, the ligand of the receptor tyrosine kinase (RTK) Met. Pre-irradiation of mouse brains increased Met-driven growth and invasiveness of orthotopically implanted glioma cells. Importantly, irradiated p21−/− mouse brains did not exhibit senescence and consequently failed to promote tumor growth. Senescent astrocytes secreted HGF to activate Met in glioma cells and promote their migration and invasion in vitro, which could be blocked by HGF-neutralizing antibodies or the Met inhibitor crizotinib. Crizotinib also slowed the growth of glioma cells implanted in pre-irradiated brains. Treatment with the senolytic drug ABT-263 (navitoclax) selectively killed senescent astrocytes in vivo, significantly attenuating growth of glioma cells implanted in pre-irradiated brains. These results indicate that SASP factors in the irradiated tumor microenvironment drive GBM growth via RTK activation, underscoring the potential utility of adjuvant senolytic therapy for preventing GBM recurrence after radiotherapy.