Elimination of Radiation-Induced Senescence in the Brain Tumor Microenvironment Attenuates Glioblastoma Recurrence.
Aniline Compounds
/ pharmacology
Animals
Antineoplastic Agents
/ pharmacology
Astrocytes
/ drug effects
Brain
/ drug effects
Cellular Senescence
Gamma Rays
/ adverse effects
Glioblastoma
/ drug therapy
Humans
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Neoplasm Recurrence, Local
/ drug therapy
Senescence-Associated Secretory Phenotype
Sulfonamides
/ pharmacology
Tumor Microenvironment
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
01 12 2021
01 12 2021
Historique:
received:
09
03
2021
revised:
22
08
2021
accepted:
22
09
2021
pubmed:
29
9
2021
medline:
11
1
2022
entrez:
28
9
2021
Statut:
ppublish
Résumé
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 radiotherapy-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. Preirradiation of mouse brains increased Met-driven growth and invasiveness of orthotopically implanted glioma cells. Importantly, irradiated p21
Identifiants
pubmed: 34580063
pii: 0008-5472.CAN-21-0752
doi: 10.1158/0008-5472.CAN-21-0752
pmc: PMC9724593
mid: NIHMS1745032
doi:
Substances chimiques
Aniline Compounds
0
Antineoplastic Agents
0
Sulfonamides
0
navitoclax
XKJ5VVK2WD
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
5935-5947Subventions
Organisme : NCI NIH HHS
ID : R01 CA197796
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA244212
Pays : United States
Organisme : BLRD VA
ID : I01 BX002559
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA241801
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA258381
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA246807
Pays : United States
Informations de copyright
©2021 American Association for Cancer Research.
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