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The Irradiated Brain Microenvironment Supports Glioma Stemness and Survival via Astrocyte-Derived Transglutaminase 2.
- Source :
-
Cancer research [Cancer Res] 2021 Apr 15; Vol. 81 (8), pp. 2101-2115. Date of Electronic Publication: 2021 Jan 22. - Publication Year :
- 2021
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Abstract
- The tumor microenvironment plays an essential role in supporting glioma stemness and radioresistance. Following radiotherapy, recurrent gliomas form in an irradiated microenvironment. Here we report that astrocytes, when pre-irradiated, increase stemness and survival of cocultured glioma cells. Tumor-naïve brains increased reactive astrocytes in response to radiation, and mice subjected to radiation prior to implantation of glioma cells developed more aggressive tumors. Extracellular matrix derived from irradiated astrocytes were found to be a major driver of this phenotype and astrocyte-derived transglutaminase 2 (TGM2) was identified as a promoter of glioma stemness and radioresistance. TGM2 levels increased after radiation in vivo and in recurrent human glioma, and TGM2 inhibitors abrogated glioma stemness and survival. These data suggest that irradiation of the brain results in the formation of a tumor-supportive microenvironment. Therapeutic targeting of radiation-induced, astrocyte-derived extracellular matrix proteins may enhance the efficacy of standard-of-care radiotherapy by reducing stemness in glioma. SIGNIFICANCE: These findings presented here indicate that radiotherapy can result in a tumor-supportive microenvironment, the targeting of which may be necessary to overcome tumor cell therapeutic resistance and recurrence. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/8/2101/F1.large.jpg.<br /> (©2021 American Association for Cancer Research.)
- Subjects :
- Animals
Astrocytes radiation effects
Brain cytology
Brain physiology
Brain Neoplasms pathology
Cell Survival physiology
Enzyme Inhibitors pharmacology
Extracellular Matrix metabolism
Extracellular Matrix radiation effects
Female
GTP-Binding Proteins antagonists & inhibitors
Glioblastoma pathology
Glioma pathology
Glioma radiotherapy
Humans
Male
Mice
Neoplasm Recurrence, Local enzymology
Neoplasm Recurrence, Local pathology
Protein Glutamine gamma Glutamyltransferase 2
Radiation Tolerance
Transglutaminases antagonists & inhibitors
Tumor Microenvironment physiology
Astrocytes enzymology
Brain radiation effects
Brain Neoplasms radiotherapy
GTP-Binding Proteins metabolism
Glioblastoma radiotherapy
Neoplastic Stem Cells physiology
Transglutaminases metabolism
Tumor Microenvironment radiation effects
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 81
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 33483373
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-20-1785