The identification and validation of GRIN2D as a novel endothelial target in colorectal cancer, and the investigation of its effects as a therapeutic tumour vaccine

Ferguson, Henry John Murray (2015). The identification and validation of GRIN2D as a novel endothelial target in colorectal cancer, and the investigation of its effects as a therapeutic tumour vaccine. University of Birmingham. M.D.

[img]
Preview
Ferguson15MD.pdf
PDF - Accepted Version

Download (4MB)

Abstract

A shortlist of candidate tumour endothelial markers was generated by Microarray comparison of differential gene expression between multiple patient-matched colorectal cancer and normal colon samples. This list was narrowed through a process of literature review, real-time quantitative polymerase chain reaction and immunohistochemistry.

Through siRNA knockdown and analysis in in vitro models of angiogenesis, it has been demonstrated that a decrease in an novel target’s expression significantly decreases cellular migration, communication and chemotaxis, without adversely affecting cell viability or proliferation in HUVEC. Vaccination with a murine Fc fusion protein in combination with Freund’s adjuvant stimulated a specific immune response to this self-antigen, by breaking immune tolerance. The resulting increase in specific IgG1 antibody titers, indicative of Th2 T-cell response, resulted in a significant reduction in physiological angiogenesis in the subcutaneous sponge assay, and a significant decrease in colorectal tumour growth in a murine subcutaneous CT26 tumour model.

The gene of interest represents a novel tumour endothelial marker in colorectal cancer. A hypothesised mechanism for the observed effects is an inhibition of endothelial calcium influx, leading to decreased angiogenic potential in tumour endothelial cells.

Type of Work: Thesis (Higher Doctorates > M.D.)
Award Type: Higher Doctorates > M.D.
Supervisor(s):
Supervisor(s)EmailORCID
Bicknell, RoyUNSPECIFIEDUNSPECIFIED
Licence:
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Immunology and Immunotherapy
Funders: None/not applicable
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
URI: http://etheses.bham.ac.uk/id/eprint/6167

Actions

Request a Correction Request a Correction
View Item View Item

Downloads

Downloads per month over past year