Use this URL to cite or link to this record in EThOS:
Title: The molecular genetics of microvascularity in paediatric high grade glioma
Author: Smith, Stuart
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2013
Availability of Full Text:
Access from EThOS:
Paediatric high grade gliomas remain poor prognosis tumours, with a median survival of only 15 months following diagnosis. Current investigation of antiangiogenic strategies, an approach which holds considerable therapeutic promise, has focused on adult glioblastoma multi forme with phase III trials targeting vascular endothelial growth factor continuing. In this study the level of neo-vascularisation within pHGG was assessed by immunohistochemistry against vascular markers such as CD31 and CD lO5. Levels of known mediators associated with increased angiogenesis were also measured and tumours segregated into low and high vascularity samples. Gene expression changes between tumours of differing vascularity were then assessed using genome wide expression profiling and validated, thus identifying novel angiogenesis related genes in pHGG. Tumours were also profiled for their levels of micro-ribonucleic acids (microRNAs) using the Nanostring array based system. Again, microRNAs were found that were significantly differentially expressed between high and low vascularity tumours. Differences were also observed in microRNA expression levels between high and low grade astrocytomas and between long and short term survivors. Modelling a complex three dimensional process such as angiogenesis is difficult in conventional monolayer cell culture. A three dimensional rotary cell culture system was optimised for the growth of macroscopic brain tumour aggregates. Characterisation of the cultures from this system revealed enhanced similarity between the cultures and actual brain tumours (compared to monolayer cultures of the same cell lines). Three dimensional aggregates showed increased drug resistance and significant up-regulation of angiogenic pathways, including fibroblast growth factor and transforming growth factor beta pathways, on real-time polymerase chain reaction and immunohistochemistry. Up-regulation of endothelial markers was also demonstrated in pure tumour cell cultures, in vitro evidence of the process of vasculogenic mimicry.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available