Validation and identification of tumour endothelial markers and their uses in cancer vaccine

Zhuang, Xiaodong (2013). Validation and identification of tumour endothelial markers and their uses in cancer vaccine. University of Birmingham. Ph.D.

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Abstract

The abnormal tumour microenvironment, which is typically hypoxic, acidic and with poor blood flow, induces the endothelial expression of genes not found on normal microvessels. By selectively targeting these tumour endothelial markers (TEMs) it is possible to induce tumour regression, presenting a potential strategy for therapeutic intervention. Potential TEMs were predicted by bioinformatics data mining. Validation of these TEM candidates identified a novel TEM CLEC14A. Functional characterization suggests a regulatory role of CLEC14A in endothelial cell migration. Inhibition of endothelial migration by CLEC14A antisera or monoclonal antibody holds therapeutic promise for the treatment of cancer. Differential gene expression analysis of freshly isolated lung tumour endothelium by 2nd generation sequencing identified 13 putative TEMs. Subsequent validation work confirmed six of which to be expressed on lung tumour vasculature. Finally, a pre-validated marker, Robo4, was investigated as a cancer vaccine. A strong antibody response was induced by delivery of pure mouse Robo4 protein or a Robo4 conjugate. The in vivo sponge assay in Robo4 vaccinated mice showed a significant reduction in vessel invasion. Tumour implantation experiments in vaccinated mice showed a marked delay in tumour growth.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):