The Research Of Notch’s Role In Glioma Stem Cells

Gliomas derived from brain glial tissue are the most common brain tumors, andfrequently leads to death. Because of their infiltrating nature and high recurrence itremains difficult to cure. Recently most researches are focused on the roles of cancerstem cells (CSCs) in the malignancy of gliomas. This subpopulation of cancer cellscapable of multi-lineage differentiation, extensive proliferation, self-renewal and gliomainitiation have been referred as glioma stem cells (GSCs). There is overwhelmingevidence that the rare GSCs with stem cell-like properties is necessary and sufficient toinitiate, maintain, and recapitulate the phenotype of the original glioma. When GSCs areeliminated from the bulk tumor mass, the initiation and growth of tumor mass areinhibited. Therefore, GSCs play an important role in glioma development and it seems tobe a prosperous target for glioma therapy.Notch signaling pathway, a closely conserved pathway across species, plays apivotal role in a series of processes, including cell proliferation, differentiation, survival,fate specification, and especially the maintenance of neural stem cells (NSCs). WhenNotch is triggered by direct interaction with its ligands, two successive site-specificproteolytic cleavages occur and release the intracellular domain of the Notch receptor(NICD) from the membrane. Then NICD translocates into the nucleus and binds the transcription factor RBP-J (the DNA recombination signal binding protein-Jκ.), formingthe NICD-RBP-J complex. This protein complex further activates the expression ofdownstream genes by recruiting other co-activators, and regulates cell fate specification,proliferation and apoptosis.Hypoxia also could promote other stem and precursor cell populations in anundifferentiated state. Culturing brain tumor cells under hypoxia conditions enlarges theirCD133-positive cell populations and results in an increase in tumorspheres formation inthe stem and non-stem cell populations. The self-renewal capability and stem-likephenotype are also promoted in the GSCs. Thus, hypoxia might be an importantcomponent of the GSCs niche.Increasing evidence has shown that there is a link between maintenance of GSCsand aberrantly activated Notch signaling.However, the exact roles of hypoxia induciblefactors and Notch signaling in the proliferation and differentiation of patient-derivedGSCshave not been clearly elucidated.Several experiments were included as follows:1. Established the primary culture of GSCs derived from patients and identified theexpression of related molecular marker.2. Blocked Notch signaling pathway on neural stem cells and detected the changesof NSCs such asneural spheres formation, self-renewal ability and multipotency.3. Blocked Notch signaling pathway on GSCs and detected the changes of GSCssuch as tumor sphere formation, self-renewal ability and multipotency.4. Blocked Notch signaling pathway on GSCs under hypoxia conditions anddetected the changes of GSCs such as tumor sphere formation, self-renewal ability andmultipotency.5. Detected molecular mechanism among Hif-1α, Hif-2αand Notch signalingpathway.Results: These data indicated that like NSCs, Notch signaling maintained thepatient-derived GSCs by promoting their proliferation, self-renewal and inhibiting theirdifferentiation.Activated Notch could inhibite the conversion of GSCs to INP-like cells. Hypoxia also could promote the proliferation and self-renewal in GSCs. When Notchwas blocked in GSCs under hypoxia conditions, the effects of hypxia on GSCs wereinhibited. Hif-1α and Hif-2α competitively bound to NICD and regulated the activationof Notch signaling pathway.