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Title: Cyclooxygenase-2 and its role in angiogenesis in colorectal cancer
Author: McArthur, David
ISNI:       0000 0001 3622 4872
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2007
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Colorectal cancer (CRC) pathogenesis is multi-factorial and complex. Gaining insight into mechanisms involved in the malignant process opens potential therapeutic and preventative interventions. This thesis details work undertaken to investigate one area ofCRC formation, namely the role that cyclooxygenase-2 (COX-2) has in its development, focussing especially on effects COX-2 has on tumour angiogenesis. COX-2 has been shown to be over-expressed in up to 85% ofCR~s and 50% of adenomas. This discovery caused excitement that COX-2 inhibitors might have roles in the prevention and treatment ofCRC. Further studies have shown that COX-2 influences malignant transformation at numerous levels, including causing reduced apoptosis, increased invasiveness and promoting angiogenesis. However, questions exist including which cells are responsible for COX-2 production, what causes COX2 expression by these cells, and how COX-2 influences cellular interactions in malignancy. Investigations, predominantly employing flow cytometry, were undertaken on CRC cell lines and disaggregated ex vivo CRC specimens. COX-2 expression by cell lines was increased by cytokines. The overall rate ofCOX-2 expression by ex vivo tumour cells was in keeping with that previously reported. However, COX-2 expression was lost when these cells were cultured for 24 hours, an effect not reversed by previously efficacious cytokines, suggesting expression in vivo is dependent on another form of cellular stimulation, possibly from neighbouring cells. High levels ofCOX-2 were discovered in paired normal colonic tissue, opening up the potential that certain individuals express COX-2 prior to cancer development, predisposing to a malignant state; these persons might benefit from COX-2 inhibitors to prevent metachronous lesions. CRC cell lines were co-cultured with human umbilical vein endothelial cells (HUVECs) to investigate COX-2 dependent effects on angiogenesis. Endothelial cell derived COX-2 increased cancer cell invasiveness by increasing ICAM-l, an effect reversed by COX-2 inhibition. COX-2 inhibition also reduced VEGF production by endothelial cells. Additionally, COX-2 levels by the two cell types were maintained at steady state, whereby an increase by HUVECs brought about a reciprocal reduction by cancer cells or vice versa.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available