Projects / Programmes
Unravelling glioma stem cell niches for novel therapeutic targets in glioblastoma patients
| Code |
Science |
Field |
Subfield |
| 3.04.00 |
Medical sciences |
Oncology |
|
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
Glioblastoma, Glioma stem cells, Bone marrow, Hematopoietic stem cells, Niches, C-X-C receptor type 4, Plerixafor, Stromal-derived factor-1?, Hypoxia, Arterioles, Subventricular zone
Researchers (15)
Organisations (3)
Abstract
Glioblastoma is the most aggressive and malignant brain tumor with a median overall survival of 20 months after diagnosis after optimal therapy (surgical tumor resection, radiotherapy, temozolomide chemotherapy and magnetic tumor treating fields). Due to outgrowth of the tumor throughout the brain, it is impossible to surgically resect the entire tumor, which results in recurrence of the tumor in patients. In glioblastoma brain tumors, cancer cells with stem cell characteristics have been described, which are called glioma stem cells (GSCs). GSCs are slowly-dividing cells that reside in special microenvironments in the tumor, called GSC niches where they are maintained as slowly-dividing cells and are protected from therapy, as radiotherapy and chemotherapy are directed against dividing cells. Quiescent GSCs escape from the effects of therapy and are held responsible for tumor recurrence in glioblastoma patients. Therefore, our major aim is to mobilize GSCs out of their protective niches to induce GSC differentiation and proliferation and their sensitization to therapy. We have previously demonstrated in human glioblastoma samples that GSC niches are hypoxic and peri-arteriolar and are similar to hematopoietic stem cell (HSC) niches in healthy human bone marrow. GSCs and HSCs are maintained and retained in hypoxic and peri-arteriolar niches in which similar chemoattrative proteins are involved, including the chemoattractant stromal-derived factor-1? and its receptor C-X-C receptor type 4 (CXCR4) which is expressed on the cell surface of GSCs/HSCs. This SDF-1?/CXCR4 axis facilitates homing of CXCR4-positive GSCs/HSCs in SDF-1?-rich niches. In this research proposal, we aim to determine whether GSC niches in glioblastoma tumors are also similar to normal neural stem cell (NSC) niches located in the subventricular zone (SVZ) of the brain which are poorly characterized. This is relevant as glioblastoma cells home in NSC niches in the SVZ where they are protected from radiotherapy. NSC niches in the SVZ-region will be characterized in normal brain samples and in brain samples that contain glioblastoma tumors. In addition, we aim to unravel why arteriolar walls are uniquely associated with GSC niches in glioblastoma tumors and HSC niches in bone marrow and which signalling pathways that are essential for the maintenance of the arteriolar identity are involved in the maintenance of GSC/HSC stemness. From a clinical point of view it is relevant to investigate whether the acquired knowledge about GSCs/HSCs can be used for the development of novel therapeutic treatment strategies. Therefore, we aim to elucidate whether the FDA-approved CXCR4 inhibitor plerixafor can be used to mobilize GSCs out of their protective niches to induce GSC differentiation and proliferation and sensitization to therapy. We expect to achieve GSC sensitization to therapy using plerixafor, as plerixafor treatment can effectively mobilize leukemic stem cells out of HSC niches resulting in their sensitization to chemotherapy. In conclusion, we aim to characterize NSC niches in normal SVZ and in glioblastoma-invaded SVZ. Furthermore, we aim to investigate why arterioles are specifically associated with GSC/HSC niches. Finally, we aim to determine whether plerixafor can be used to sensitize GSCs to standard glioblastoma therapies.
