Advances in the treatment of ovarian cancer have had a limited impact on prognosis over recent decades. Alternatives to the traditional surgical and chemotherapeutic approach are being sought. Many novel therapies relate to a greater understanding of the molecular changes which occur during carcinogenesis and the development of targeted therapies to exploit these abnormalities. The aim of this thesis was to investigate the prognostic significance of markers relating to tumour immunology, angiogenesis and apoptosis, through the use of Tissue Microarray Technology. 339 cases of ovarian cancers diagnosed between 1982 and 1997 were assessed. Tumours were analysed immunohistochemically for expression of components of the IFNy (IFNGR1, STAT1, p27, caspase 1), TRAIL (DR4 and DR5) and angiogenic (VEGF) pathways. Loss of expression of IFNGR1 was an independent predictor of poor prognosis, although STAT 1 was not. High levels of cytoplasmic and nuclear p27 expression were associated with a reduced survival; cytoplasmic was independently prognostic. Tumours with reduced levels of caspase 1 had improved survival. These results suggest that only patients expressing IFNGR1 may benefit from IFNy therapy and provides evidence of immunoediting in ovarian cancer. DR4 and DR5 did not predict prognosis suggesting that the TRAIL pathway may not be significant in ovarian cancer apoptosis with implications for TRAIL-related therapy. High levels of VEGF occurred infrequently, being an independent marker of poor prognosis. This may identify a group of patients who may preferentially benefit from anti-angiogenic therapy. The thesis illustrates that ovarian cancers are heterogeneous and variations in expression of protein markers can predict tumour behaviour and stratify for therapy. Future targeted therapies may be selected on the basis of an immunohistochemical profile which predicts the pathways that are still functioning. New therapies as they arise should be trialed and targeted to tumours expressing the appropriate molecular markers.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:559526 |
| Date | January 2010 |
| Creators | Duncan, Timothy Jake |
| Publisher | University of Nottingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://eprints.nottingham.ac.uk/11326/ |
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