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Title: MRI and histological analysis of brain metastasis and the effect of systemic inflammation
Author: Hamilton, Alastair M. A.
ISNI:       0000 0004 2747 1638
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2013
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Background: Brain metastasis is a leading cause of cancer mortality and affects 20-40% of all cancer patients. The BBB is responsible for isolation and protection of the brain parenchyma from many diagnostic and therapeutic agents. New molecular agents that target tumour-associated VCAM-1 expression on the brain endothelium show improvements in the early diagnosis of brain metastasis. The vascular endothelium of the CNS plays an important role in the maintenance of the brain microenvironment and possibly aids the extravasation of tumour cells via expression of CAMs. Aims: Using the breast carcinoma-derived 4T1 cell line, syngeneic to BALB/c mice, this work aimed (i) to determine the level of colocalisation between VCAM-1 expression at sites of brain metastasis and the presence of VCAM-MPIO-induced hypointensities in MR datasets; (ii) to describe the normal developmental characteristics of the intracardial BALB/c-4T1 brain metastatic model in the absence of overt inflammation; (iii) to test the effects of an adenovirus-induced systemic inflammatory challenge on metastatic uptake and development in the brain. Results: The level of correspondence of VCAM-MPIO-derived hypointensities with VCAM-1 expression at the tumour site was found to be dependent on the size of metastasis. An improved method for detection of VCAM-MPIO hypointensities using an automated method has been presented. Tumours were found to develop preferentially on venous rather than arteriolar blood vessels, and showed greater and lesser abundance in different anatomical brain regions. Adenovirus injection was found to cause an upregulation of a range of peripheral pro-inflammatory cytokines, and expression of VCAM-1 on cerebral vasculature, preferentially on arteriolar blood vessels. Both pre- and post-treatment with adenovirus caused a two-fold reduction in tumour numbers and altered developmental characteristics of established tumours, although no significant differences were observed in VCAM-MPIO hypointensities in MR datasets. Conclusions: The development of molecular MRI approaches to target VCAM-1 expression at the site of brain metastases has improved the sensitivity of tumour detection. 4T1-GFP metastasis to the brain is specific both to anatomical sites and to regions of the vascular bed, suggesting differences in vascular morphology and/or signalling dynamics in these locations. The changes in tumour number and morphology as a result of systemic inflammation suggest an anti-tumour effect of adenoviral treatment and, given the role of the systemic immune system and its importance in the development of immunotherapies, possible future directions for research.
Supervisor: Sibson, Nicola R.; Anthony, Daniel C. Sponsor: EPSRC ; CRUK ; MRC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Biology ; Oncology ; Viruses ; Tumours ; blood-brain barrier ; immunology ; metastasis ; image analysis