胶质母细胞瘤
医学
脑瘤
放射治疗
肿瘤进展
小胶质细胞
癌症
作者
Eliot Fletcher-Sananikone,Suman Kanji,Nozomi Tomimatsu,Luis Fernando Macedo Di Cristofaro,Rahul K. Kollipara,Debabrata Saha,John Floyd,Patrick Sung,Robert Hromas,Terry C. Burns,Ralf Kittler,Amyn A. Habib,Bipasha Mukherjee,Sandeep Burma
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2021-09-27
卷期号:81 (23): 5935-5947
被引量:2
标识
DOI:10.1158/0008-5472.can-21-0752
摘要
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.
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