The Irradiated Brain Microenvironment Supports Glioma Stemness and Survival via Astrocyte-Derived Transglutaminase 2

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.

Glioblastoma Microenvironment: From an Inviolable Defense to a Therapeutic Chance

“…It is still unclear if GSCs derived from altered NSCs or mutated glioma cells ( 98 ). Glioblastoma Stem Cells are surely associated with GBM progression and recurrence after surgery ( 99 , 100 ). The surface marker CD133 is one of the most adopted markers to recognize GSCs.…”

Radiotherapy of High-Grade Gliomas: First Half of 2021 Update with Special Reference to Radiosensitization Studies

“…Irradiation of the brain can lead to the onset of a tumor-friendly microenvironment. Astrocytes, when pre-irradiated, increase the stemness and survival of co-cultured glioma cells [37], and mice subjected to IR prior to glioma cell implantation may develop more aggressive tumors. The extracellular matrix of irradiated astrocytes, and in particular its transglutaminase 2 component, were found to be important factors in promoting the stemness and aggressiveness of HGGs.…”

“…The extracellular matrix of irradiated astrocytes, and in particular its transglutaminase 2 component, were found to be important factors in promoting the stemness and aggressiveness of HGGs. Transglutaminase 2 levels are increased after IR in vivo and in recurrent HGG, and transglutaminase 2 inhibitors can counteract glioma proliferation [37]. The impact of RT on the microenvironment of experimental HGGs may also involve immune suppression [38].…”

Old Stars and New Players in the Brain Tumor Microenvironment

“…Radiation, for instance, can stimulate the release of multiple factors by reactive astrocytes. These factors can support glioma stemness and promote tumor recurrence (Berg et al, 2021). Astrocytes collaborate with microglia to clear oncolytic viral particles, leading to severe implications for the therapeutic use of oncolytic viruses in gliomas (Kober et al, 2015).…”