In vitro functional studies of the tumour vascular target PCDH7 and identification of novel tumour vascular targets in colorectal cancer

Korzystka, Aleksandra (2019). In vitro functional studies of the tumour vascular target PCDH7 and identification of novel tumour vascular targets in colorectal cancer. University of Birmingham. Ph.D.

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Abstract

Protocadherin 7 (PCDH7) is a member of PCDHs belonging to the cadherin superfamily. It was recently identified as potential tumour endothelial maker (TEM). Although it is expressed in many solid tumours, its function in endothelial cells and its binding partner(s) on endothelial cell surface are unknown. Thus a major aim of this thesis was to determine the role of its extracellular domain (ECD) in endothelial cells and to potentially identify novel ligand(s) of its ECD on endothelial cell surface. Recombinant human Fc fused hPCDH7 ECD significantly inhibited endothelial network formation, cell proliferation and chemotaxis in vitro. This was mediated by the first five N-terminal cadherin repeats of the ECD. However, no ligands of the ECD were identified. A second part of this thesis involved the identification of novel TEMs from colorectal cancer. Apelin (APLN), endothelial cell-specific molecule-1 (ESM-1), matrix metalloproteinase-12 (MMP12) and epiregulin (EREG) identified as potential candidates will be further validated. Additionally, the angiogenic potential of protein C receptor (PROCR), chromosome 1 open reading frame 54 (C1ORF54) and stabilin 1 (STAB1) which were enriched in tumour endothelium was investigated, with a role for PROCR in endothelial network formation identified. The findings of this thesis enhance our understanding of the molecular signature of tumour endothelial cells and lay the foundation for the potential development of novel anti-cancer therapies.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):