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Title: Anatomical and vascular imaging with high frequency ultrasound in preclinical models of colorectal cancer
Author: Marston, Gemma
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2012
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Colorectal cancer (CRC) is one of the most common malignancies in the western world and is the third most common cause of cancer related deaths in the UK. It has a good 5 year survival rate if the cancer is diagnosed at an early stage - 93% for Dukes' stage A; however, for late stage metastatic disease, this falls to only 7%. Improvements in treatment for metastatic disease, detection and screening are required to combat these low survival rates. Preclinical models, and in particular mouse models, are invaluable for studying the mechanisms which initiate tumour development and progression. Many models of CRC exist, including models of hereditary and sporadic CRC, including human CRC cell xenografts which support rapid tumour growth, allowing for relatively fast, short term studies and investigations into novel therapeutics. The ApcMin/+ mouse model recapitulates the early stages of human CRC development, with many polyps developing throughout the small intestine and colon. This project investigated the use of non-invasive imaging with high frequency ultrasound to provide anatomical information on the abdomen, and specifically the colon, of C57BI/6J mice, and the reproducibility of a protocol to measure the colon wall thickness in vivo. Once established, these techniques were then used to detect polyps in aged (170±34 days) and 90 day old ApcMin/+. mice, showing that this technique could be used with sensitivity and specificity of 48% and 100%, respectively. This project also investigated the feasibility of using contrast enhanced high frequency ultrasound to monitor the growth of human CRC cell xenografts and qualitatively and quantitatively assess their longitudinal vascular development in vivo. These data were then used as the basis of an intervention study, which incorporated the vascular disruptive agent Combretastatin A-4 into the CE-HFUS imaging protocols in order to assess the immediate vascular kinetic impact of CA4. This showed that CE-HFUS can detect and quantitate changes in tumour vascular kinetics in vivo following treatment with a known agent, suggesting that it may be useful in preclinical drug development. The work in this Thesis has demonstrated that C57BI/6 mouse colon wall thickness can be accurately determined in vivo, in an operator independent manner. Following on from the characterisation of colon wall thickness in wild type mice; this Thesis has shown for the first time that it is possible to identify colonic polyps in ApcMin/+ mice in vivo in both 90 day old and older age mice. Work in this Thesis has also characterised i for the first time with CE HFUS the blood flow kinetics and vascular perfusion of HCT116 CRC xenograft tumours in a longitudinal study. Building on this work, this Thesis has shown for the first time disruption in blood flow kinetics to HCT116 CRC xenograft tumours after exposure to CA4.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available