William Collier

Title: The effect of hypoxia on TRAIL mediated pancreatic cancer cell apoptosis

Summary:

The incidence of pancreatic cancer (PC) continues to rise in the UK and is associated with very poor prognosis. Currently less than 3% of patients diagnosed with PC survive for more than 5 years. Having learnt how poor the survival for PC patients was during my clinical placements in medical school, I was very motivated to pursue this research. Additionally, I have always had an interest in both the gastroenterological system and cancer related medicine.

Current management strategies are failing to improve this poor prognosis. Tumour Necrosis Factor-related Apoptosis Inducing Ligand (TRAIL) can induce cell death in PC cells and is considered a promising therapeutic agent.

My project investigated whether hypoxia and/or a cellular process called autophagy affect TRAIL mediated cell death in PC cells. Specifically, I assessed whether hypoxia and/or autophagy mediated resistance to TRAIL induced cell death. This also involved characterising human PC tissue for TRAIL receptor expression and autophagy.

The aims were threefold. To determine the response of PC cells to hypoxia, including levels of cell death, autophagy and TRAIL receptor expression, the effect of TRAIL agonism and autophagy inhibition on PC cells in hypoxia and establish PC tissue expression of autophagy and TRAIL/TRAIL receptors.

The findings in this study implicate autophagy activation and altered TRAIL receptor expression in hypoxia as mechanisms contributing to TRAIL resistance and thus PC cell survival. These findings demonstrate inhibition of autophagy is a potential mechanism to sensitise PC cells to TRAIL induced apoptosis and overcome the clinically observed TRAIL resistance.