Abstract
Glioblastoma is a uniformly fatal cancer with short prognosis and no available cure. Most people diagnosed and treated with chemotherapy, survive for 15-18 months. Maximal surgical resection, followed by aggressive radiotherapy and chemotherapy provide short survival extensions, followed by universal recurrence and fatality. Glioma stem cells (GSCs), reminiscent of transformed neural stem cells (NSCs) are believed to be a major source of tumour resistance and reestablishment after therapy. Glioblastoma is frequently compared to a neurodevelopmental hierarchy in which key signalling pathways for reprogramming and self-renewal can be exploited. Insulin-like growth factor binding protein 2 (IGFBP-2) overexpression is associated with short prognosis and survival in glioblastoma. However, its functions within the tumour are poorly understood. High expression in the foetal brain at regions of complex morphogenesis and close extracellular proximity to NSCs in the adult brain point to a key role in NSC maintenance. This thesis explored the functions of IGFBP-2 within the stem cell compartment of glioblastoma.Analysis of bulk isocitrate dehydrogenase (IDH)-wildtype tumour tissue, single-cell glioblastoma and stem cell data identified IGFBP-2 overexpression in neoplastic and stem cell types. Moreover IGFBP-2 expression was positively correlated with key stem cell maintenance genes. Differentiation studies indicated that high IGFBP-2 abundance is required for the self-renewing NSC/ GSC state and that high levels of secretion could support self-renewal of neighbouring GSCs. Furthermore, IGFBP-2 led to signal transducer and activator of transcription 3 (STAT3) pathway activation in line with other studies. Our results show that extracellular IGFBP-2 may drive this pathway in GSCs.
Functional studies highlighted the heterogenous morphology, proliferation, and migration of GSCs. Different growth patterns and rapid migration rates highlighted the complexity and the requirement for further exploration by several approaches.
| Date of Award | 18 Mar 2025 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Kathreena M Kurian (Supervisor), Claire M Perks (Supervisor) & Richard M Martin (Supervisor) |