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Title: Selective permeabilisation of the blood-brain barrier during brain metastasis via TNFR1
Author: Karali, Christina Simoglou
ISNI:       0000 0004 7966 2671
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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The presence of an intact, impermeable blood-brain barrier (BBB) during the early stages of metastatic colonisation significantly limits early detection and effective treatment of brain metastasis. Systemic tumour necrosis factor (TNF) administration transiently permeabilises the metastasis-associated vasculature, whilst retaining the integrity of the surrounding the BBB. This approach enables both the enhanced detection of metastatic colonies with contrast-enhanced MRI and the improved delivery of therapeutically relevant molecules to the tumour site. The aim of this thesis was to unravel the mechanism underlying the TNF-induced BBB breakdown. TNFR1, but not TNFR2, is upregulated on tumour-associated vasculature in experimental models, human brain metastasis resections and endothelial cells co-cultured with metastatic tumour cells (breast, lung or melanoma) or stimulated with relevant tumour cell conditioned media. Treatment of an endothelial monolayer with either TNF or a TNR1-selective mutein increased permeability, which was eliminated in TNFR1-silenced endothelial cells stimulated with TNF. TNFR2 silencing did not alter TNF-induced endothelial permeability. In vitro studies revealed that the blockade of the Ras/PI3K/Akt/mTOR signalling cascade, alongside components of the RhoGTPase family and NFκΒ pathway prevented the TNF-induced permeabilisation of the brain endothelium. On the contrary, targeting of the MAPK pathways had no effect on TNF-induced permeabilisation. The results of this study suggest that TNF-induced BBB permeabilisation is TNFR1-mediated and involves activation of the Ras/PI3K, the Ras/ RhoGTPases and NFκΒ pathways. These findings support the concept that TNFR1-targeted agents may provide a sensitive and specific means to selectively and transiently modulate the BBB at sites of brain micrometastasis.
Supervisor: Sibson, Nicola ; Anthony, Daniel Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available