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Title: Cathepsin S as a potential therapeutic target in radioresistant glioblastoma
Author: Foster, Robyn
ISNI:       0000 0004 6425 3074
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2017
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Glioblastoma (GBM) is a highly malignant tumour with an extremely poor patient prognosis. It is characterised by its highly invasive nature and resistance to current therapies, including radiotherapy. Despite multimodal therapy, GBM almost always recurs. Cat S is a cysteine cathepsin which may be relevant in tumour invasion and radioresistance. The stem cell hypothesis suggests that there is a subpopulation of stem-like glioma cells (GSCs) which are intrinsically resistant to therapies, are able to repopulate the tumour and cause recurrence. The aim of this thesis was to investigate the effect of Cat S knockdown and inhibition on GBM non-stem cell and GSC invasion and radiation resistance. The results in this thesis show that the effect of Cat S knockdown on GBM cell lines is both complex and context-dependent. Non-stem cells showed reduction in invasion and radioresistance with Cat S knockdown. U87 GSCs showed similar results to non-stem cells, while LN229 GSCs showed no effect of Cat S knockdown on invasion or radioresistance. Further exploration showed that Cat S-like activity was not affected by Cat S knockdown in LN229 GSCs. Proliferation, plating efficiency, stem cell markers and cell cycle proteins were all altered with Cat S knockdown. These results suggest that one or multiple signalling pathways were affected by Cat S knockdown. A small molecule inhibitor of Cat S replicated many of the findings from Cat S knockdown. This project showed that Cat S knockdown or inhibition reduced invasion and radioresistance of GBM non-stem cells, and while effective in U87 GSCs, there was no consistent effect in LN229 GSCs. The reason for this remains to be elucidated, but observations suggest that one or multiple signalling pathways were affected which impacted on wide-ranging characteristics. These data support the hypothesis that Cat S is a potential therapeutic target in GBM, though further research is required to elucidate which patients may benefit.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available