Glioma Stem-like Cells Proliferation Research Articles

Induction of cell-cycle arrest and apoptosis in glioblastoma stem-like cells by WP1193, a novel small molecule inhibitor of the JAK2/STAT3 pathway

Glioma stem-like cells (GSCs) may be the initiating cells in glioblastoma (GBM) and contribute to the resistance of these tumors to conventional therapies. Development of novel chemotherapeutic agents and treatment approaches against GBM, especially those specifically targeting GSCs are thus necessary. In the present study, we found that a novel Janus kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) pathway inhibitor (WP1193) significantly decreased the proliferation of established glioma cell lines in vitro and inhibit the growth of glioma in vivo. To test the efficacy of WP1193 against GSCs, we then administrated WP1193 to GSCs isolated and expanded from multiple human GBM tumors. We revealed that WP1193 suppressed phosphorylation of JAK2 and STAT3 with high potency and demonstrated a dose-dependent inhibition of proliferation and neurosphere formation of GSCs. These effects were at least due in part to G1 arrest associated with down-regulation of cyclin D1 and up-regulation of p21( Cip1/Waf-1 ). Furthermore, WP1193 exposure decreased expression of stem cell markers including CD133 and c-myc, and induced cell death in GSCs through apoptosis. Taken together, our data indicate that WP1193 is a potent small molecule inhibitor of the JAK2/STAT3 pathway that shows promise as a therapeutic agent against GBM by targeting GSCs.

Glioma Stem Cells and their Therapy Resistance

Glioblastoma multiforme (GBM) is the most highly invasive and malignant primary brain tumor in humans with median survival after diagnosis as low as 12-15 months. The poor prognosis of GBM is attributable to its resistance to current therapeutic approaches, consisting of maximal debulking surgery, chemotherapy with temozolomide, and radiotherapy. Amongst the heterogeneous population of tumor cells found in GBM, a self-renewing and proliferating cell type known as glioma stem-like cells (GSC) has been identified as a potential source for glioma therapy resistance. It has been well documented that current therapies fail to effectively eliminate GSC from the tumor population. This contributes to the virtually inevitable tumor recurrence in GBM patients following treatment. Therefore, GSC provide a particularly attractive target for the development of future therapies. This review highlights several proposed mechanisms behind therapy resistant glioma cells including DNA repair mechanisms, cell cycle checkpoints, drug efflux processes, and the role of the tumor microenvironment. Furthermore, several therapeutic strategies to target genes or pathways specific to GSC survival and proliferation will be discussed.

P53 Directly Represses Id2 to Inhibit the Proliferation of Neural Progenitor Cells

Neural progenitor cells (NPCs) have the capacity to proliferate and give rise to all major central nervous system cell types and represent a possible cell of origin in gliomagenesis. Deletion of the tumor suppressor gene Tp53 (p53) results in increased proliferation and self-renewal of NPCs and is a common genetic mutation found in glioma. We have identified inhibitor of DNA binding 2 (Id2) as a novel target gene directly repressed by p53 to maintain normal NPC proliferation. p53((-/-)) NPCs express elevated levels of Id2 and suppression of Id2 expression is sufficient to inhibit the increased proliferation and self-renewal which results from p53 loss. Elevated expression of Id2 in wild-type NPCs phenocopies the behavior of p53((-/-)) NPCs by enhancing NPC proliferation and self-renewal. Interestingly, p53 directly binds to a conserved site within the Id2 promoter to mediate these effects. Finally, we have identified elevated Id2 expression in glioma cell lines with mutated p53 and demonstrated that constitutive expression of Id2 plays a key role in the proliferation of glioma stem-like cells. These findings indicate that Id2 functions as a proproliferative gene that antagonizes p53-mediated cell cycle regulation in NPCs and may contribute to the malignant proliferation of glioma-derived tumor stem cells.