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Title: Genomic and post-genomic studies in endometrial cancer
Author: Holland, C. M.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2004
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Genomic abnormalities lead to aberrant cell growth and signalling, contributing to the development of malignancy. Growth and metastasis also require the development of tumour vasculature. The VEGFs and angiopoietins are growth factor families central to this process. This thesis examines their expression in endometrial cancer. Genomic and post-genomic studies are used to broaden the investigation of angiogenesis and include related pathways. Using in situ hybridisation VEGF-A mRNA was detected in epithelial cancer cells but not pre-malignant and benign endometrium while VEGF-B was localised to both epithelial and stromal cells and was most abundant in benign endometrium. These findings suggest that VEGF-B may modulate the actions of VEGF-A by occupying receptors. Larger, gene microarray studies confirmed the differential expression of angiogenic factors and also identified a distinct set of coherently regulated genes in endometrial cancers. Within this gene set, PPARα, a transcription factor regulating fatty acid metabolism, was over-expressed in cancers unlike RXRβ, a heterodimerisation partner, which was down-regulated. A PPARα ligand altered proliferation and apoptosis of endometrial cancer cells suggesting that a normal PPARα/RXRβ ratio helps maintain cellular growth control. In conclusion, this work has defined the pattern of expression of the VEGF and angiopoieten families in endometrial cancer and identified VEGF-B as a possible modulator of VEGF-A action. Abnormalities of the fatty acid metabolic pathway have also been identified as a feature of endometrial cancer. Furthermore, an activating ligand for PPARα, a key factor in this pathway, exerted beneficial effects on the growth of endometrial cancer cells. PPARα ligands may therefore have therapeutic potential in endometrial cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available