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Induction of senescence in primary glioblastoma cells by serum and TGF?.

ABSTRACT: Glioblastoma is the most common type of adult brain tumour and has a median survival after diagnosis of a little more than a year. Glioblastomas have a high frequency of mutations in the TERT promoter and CDKN2A locus that are expected to render them resistant to both replicative and oncogene-induced senescence. However, exposure of PriGO8A primary glioblastoma cells to media with 10% serum induced a senescence-like phenotype characterized by increased senescence-associated ? galactosidase activity, PML bodies and p21 and morphological changes typical of senescence. Microarray expression analysis showed that 24?h serum exposure increased the expression of genes associated with the TGF? pathway. Treatment of PriGO8A cells with TGF? was sufficient to induce senescence in these cells. The response of PriGO8A cells to serum was dependent on basal expression of the TGF? activator protein thrombospondin. Primary glioblastoma cells from three additional patients showed a variable ability to undergo senescence in response to serum. However all were able to undergo senescence in response to TGF?, although for cells from one patient this required concomitant inhibition of Ras pathway signalling. Primary glioblastoma cells therefore retain a functional senescence program that is inducible by acute activation of the TGF? signalling pathway.

SUBMITTER: Kumar R

PROVIDER: S-EPMC5438350 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Induction of senescence in primary glioblastoma cells by serum and TGFβ.

Kumar Ritesh R Gont Alexander A Perkins Theodore J TJ Hanson Jennifer E L JEL Lorimer Ian A J IAJ

Scientific reports 20170519 1

Glioblastoma is the most common type of adult brain tumour and has a median survival after diagnosis of a little more than a year. Glioblastomas have a high frequency of mutations in the TERT promoter and CDKN2A locus that are expected to render them resistant to both replicative and oncogene-induced senescence. However, exposure of PriGO8A primary glioblastoma cells to media with 10% serum induced a senescence-like phenotype characterized by increased senescence-associated β galactosidase activ ...[more]

PMID: 28526854

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Project description:BackgroundGlioblastoma (GB) is considered one of the most lethal tumors. Extensive research at the molecular level may enable to gain more profound insight into its biology and thus, facilitate development and testing of new therapeutic approaches. Unfortunately, stable glioblastoma cell lines do not reflect highly heterogeneous nature of this tumor, while its primary cultures are difficult to maintain in vitro. We previously reported that senescence is one of the major mechanisms responsible for primary GB cells stabilization failure, to a lesser extent accompanied by apoptosis and mitotic catastrophe-related cell death.MethodsWe made an attempt to circumvent difficulties with glioblastoma primary cultures by testing 3 different approaches aimed to prolong their in vitro maintenance, on a model of 10 patient-derived tumor specimens.ResultsTwo out of ten analyzed GB specimens were successfully stabilized, regardless of culture approach applied. Importantly, cells transduced with immortalizing factors or cultured in neural stem cell-like conditions were still undergoing senescence/apoptosis. Sequential in vivo/in vitro cultivation turned out to be the most effective, however, it only enabled to propagate cells with preserved molecular profile up to 3rd mice transfer. Nevertheless, it was the only method that impeded these phenomena long enough to provide sufficient amount of material for in vitro/in vivo targeted analyses. Interestingly, our data additionally demonstrated that some subpopulations of several stabilized GB cell lines undergo idiopathic senescence, however, it is counterbalanced by simultaneous proliferation of other cell subpopulations.ConclusionsIn the majority of primary glioma cultures, there has to be an imbalance towards apoptosis and senescence, following few weeks of rapid proliferation. Our results indicate that it has to be associated with the mechanisms other than maintenance of glioblastoma stem cells or dependence on proteins controlling cell cycle.

Dataset Information

Induction of senescence in primary glioblastoma cells by serum and TGF?.

Publications

Induction of senescence in primary glioblastoma cells by serum and TGFβ.

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