Senescence from glioma stem cell differentiation promotes tumor growth

Abstract

Glioblastoma (GBM) is a lethal brain tumor composed of heterogeneous cellular populations including glioma stem cells (GSCs) and differentiated non-stem glioma cells (NSGCs). While GSCs are involved in tumor initiation and propagation, NSGCs’ role remains elusive. Here, we demonstrate that NSGCs undergo senescence and secrete pro-angiogenic proteins, boosting the GSC-derived tumor formation in vivo. We used a GSC model that maintains stemness in neurospheres, but loses the stemness and differentiates into NSGCs upon serum stimulation. These NSGCs downregulated telomerase, shortened telomeres, and eventually became senescent. The senescent NSGCs released pro-angiogenic proteins, including vascular endothelial growth factors and senescence-associated interleukins, such as IL-6 and IL-8. Conditioned medium from senescent NSGCs promoted proliferation of brain microvascular endothelial cells, and mixed implantation of GSCs and senescent NSGCs into mice enhanced the tumorigenic potential of GSCs. The senescent NSGCs seem to be clinically relevant, because both clinical samples and xenografts of GBM contained tumor cells that expressed the senescence markers. Our data suggest that senescent NSGCs promote malignant progression of GBM in part via paracrine effects of the secreted proteins.

Molecular subtypes and differentiation programmes of glioma stem cells as determinants of extracellular vesicle profiles and endothelial cell‐stimulating activities

“…For these experiments we chose cell lines GSC 157 and GSC 83, which exhibit PN and MES characteristics, respectively, and could be cultured under conditions known to favour either stemness or differentiation [9]. As previously characterized [16,37], the non-adherent PN GSCs formed tight multicellular spheres with extensive cell-cell contacts (Figure 2(a-b)), expressed high levels of the stem cell marker, prominin 1 (CD133), and almost no CD44 (Figure S3 A-B). They were also virtually negative for glial fibrillary acidic protein (GFAP), which is normally expressed by more mature astrocytes (Figure S3C-D).…”

G-quadruplex ligand-induced DNA damage response coupled with telomere dysfunction and replication stress in glioma stem cells

“…GBM146 and 157 GSCs were maintained in serum-free sphere medium, and NSGCs were obtained from these GSCs as previously described [19,20]. Cell proliferation was evaluated using a CellTiter-Glo Luminescent Cell Viability Assay (Promega, Fitchburg, WI, USA).…”

“…Cell proliferation was evaluated using a CellTiter-Glo Luminescent Cell Viability Assay (Promega, Fitchburg, WI, USA). Flow cytometry was performed as described [20]. …”

Reconstructing the Molecular Life History of Gliomas

“…Aforementioned studies supporting the cancer stem cell hypothesis suggest that multiple cellular populations exist within a tumor, including a self-renewing cancer stem cell population and a less-proliferative differentiated population. A recent paper demonstrated that cells derived from glioma stem cells may differentiate and subsequently undergo senescence [198]. We speculate that phase V tumor cells represent cancer stem cells that may give rise to more differentiated, phase IV cells (Figure 5A).…”