O'Rourke, Joanne (2024). Contribution of the endothelial protein CLEC14A to the pathogenesis of liver disease and liver cancer. University of Birmingham. Ph.D.
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O'Rourke2024PhD.pdf
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Abstract
The endothelium is a crucial component of the liver microenvironment. Hepatic sinusoidal endothelial cells (HSEC) that line the liver sinusoids form a unique specialised microvasculature. I investigated the expression of CLEC14A in the human liver and described how it is upregulated on sinusoidal endothelium in hepatocellular carcinoma (HCC). It can also be found on larger vessels supplying HCC and in bridging fibrosis in chronic liver disease. Flow-based adhesion assays with HSEC revealed that CLEC14A mediates the adhesion of neutrophils and in vitro angiogenesis studies revealed that CLEC14A promotes the migration and tube formation of HSEC.
I have evaluated CLEC14A as a serum biomarker in HCC, however, the detection of CLEC14A in the serum of cirrhotic non-HCC patients limits its value as a HCC surveillance tool in this cohort. I have shown that low shear stress upregulates CLEC14A on HSEC and CLEC14A is also upregulated by hypoxia and these conditions have the opposite effect on Multimerin 2, a ligand of CLEC14A. I have also narrowed down the region of Multimerin 2 where it interacts with CD248 showing that it is at a distinctly different site from where VEGF binds MMRN2.
I have presented digital spatial profiling data that support a role for CLEC14A in HCC tumour angiogenesis and suggest it may also influence the recruitment of natural killer cells. In addition, high CLEC14A expression is associated with poor tumour differentiation and vascular invasion. This work has indicated that CLEC14A is a novel target in pathological angiogenesis in liver disease and HCC, and also contributes to the immune microenvironment in liver disease.
| Type of Work: | Thesis (Doctorates > Ph.D.) | |||||||||
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| Award Type: | Doctorates > Ph.D. | |||||||||
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| Licence: | All rights reserved | |||||||||
| College/Faculty: | Colleges (former) > College of Medical & Dental Sciences | |||||||||
| School or Department: | School of Immunology and Immunotherapy | |||||||||
| Funders: | Cancer Research UK | |||||||||
| Subjects: | R Medicine > R Medicine (General) | |||||||||
| URI: | http://etheses.bham.ac.uk/id/eprint/14758 |
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