Astrocytes enhance glioblastoma growth

Abstract

Glioblastoma (GBM) is a deadly disease with a need for deeper understanding and new therapeutic approaches. The microenvironment of glioblastoma has previously been shown to guide glioblastoma progression. In this study, astrocytes were investigated with regard to their effect on glioblastoma proliferation through correlative analyses of clinical samples and experimental in vitro and in vivo studies. Co‐culture techniques were used to investigate the GBM growth enhancing potential of astrocytes. Cell sorting and RNA sequencing were used to generate a GBM‐associated astrocyte signature and to investigate astrocyte‐induced GBM genes. A NOD scid GBM mouse model was used for in vivo studies. A gene signature reflecting GBM‐activated astrocytes was associated with poor prognosis in the TCGA GBM dataset. Two genes, periostin and serglycin, induced in GBM cells upon exposure to astrocytes were expressed at higher levels in cases with high “astrocyte signature score”. Astrocytes were shown to enhance glioblastoma cell growth in cell lines and in a patient‐derived culture, in a manner dependent on cell–cell contact and involving increased cell proliferation. Furthermore, co‐injection of astrocytes with glioblastoma cells reduced survival in an orthotopic GBM model in NOD scid mice. In conclusion, this study suggests that astrocytes contribute to glioblastoma growth and implies this crosstalk as a candidate target for novel therapies.

The irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived Transglutaminase 2

“…Tumor-associated astrocytes react to the GBM microenvironment with an altered phenotype, 60 and were recently shown to promote glioma growth. 32,61 We show here that astrocytes secrete TGM2 in response to radiation, which supports stemness and radiation resistance of GBM cells. Inhibition of TGM2 decreased survival of tumor cells in an ex vivo organotypic slice model of GBM, and was previously shown to increase survival in a glioma xenograft model.…”

“…31 Several of these cell types have been shown to actively contribute to glioma aggressiveness. 32,33 Little is known about how these cells respond to radiotherapy, and how they in turn might affect the associated glioma cells after irradiation. We sought to determine whether irradiation of the brain tumor microenvironment might affect the phenotype and therapeutic response of glioma cells.…”

The Organoid Era Permits the Development of New Applications to Study Glioblastoma

“…They also displayed a new potential role of microglia in glioblastoma: microglia appear to modulate sensitivity to cytotoxic agents conferring drug resistance to the tumor. Similarly, another study hypothesizes that astrocytes in TME behave like microglia by reducing cancer sensitivity to drugs and interactions between astrocytes and GB cells could be associated with increased growth and invasion of the tumor [96]. To confirm this, it was demonstrated that the direct contact between 3D co-culture of astrocytes and GB cells enhances glioblastoma formation [97].…”

Niche-derived soluble DLK1 promotes glioma growth

“…Indeed, soluble DLK1 secreted from astrocytes was recently shown to be a critical component of the subventricular zone neural stem cell niche [11] . Astrocytes represent a prominent cell type in the brain tumor microenvironment [17] , and recent studies revealed that DLK1 is one of the top upregulated genes in tumor-associated astrocytes of high-grade vs low-grade gliomas [18] . The regulation of DLK1 expression is poorly understood, but some elements of the brain tumor microenvironment such as hypoxia have been shown to drive DLK1 expression [19 , 20] .…”