Exploring the role of lipoxygenases in oesophageal cancer and the anti-angiogenic potential of novel lipoxgenase inhibitors

Abstract

Over the past decade there has been a dramatic increase in the incidence of oesophageal cancer in Ireland, which has the third highest incidence rate in Europe. This is mainly due to rising numbers of the oesophageal adenocarcinoma (OAC) subtype which is strongly associated with obesity. Despite major improvements to patient outcomes through more advanced chemo-radiation therapy regimes, fewer than 20% of oesophageal cancer patients remain alive 5 years after their diagnosis. Clearly, this cancer represents a burden to the Irish health system and a challenge to clinicians and scientists alike. Thus an increased understanding of the molecular mechanisms underlying this cancer is invaluable and will lead to the identification of novel biomarkers, for both the earlier detection and molecular therapeutic targeting of this disease. 5-lipoxygenase (5-LO) and platelet type 12-lipoxygenase (12-LO) are two enzymes involved in the metabolism of arachidonic acid to pro-inflammatory bioactive lipids signalling molecules known as eicosanoids. Both 5-LO and 12-LO and their metabolites have been linked to cancer with roles in inflammation, tumourigenesis, angiogenesis and survival reported. The overall aim of this thesis was to explore the role of 5-LO and 12-LO in OAC, which is poorly understood. The clinical significance of 5-LO and 12-LO activity in OAC was investigated in a number of different human biological sample types including OAC biopsy RNA, tumour tissue microarrays (TMA) and serum. Given the newly emerged role of 5-LO signalling in metabolic syndrome and obesity, a role of 5-LO in obesity-associated OAC was also explored in OAC tumour and fat tissue.