On the Role of Polyamines and Microvesicles in Tumour Development. Regulation by Hypoxia and Implications for Therapeutic Intervention of Cancer

Abstract: Novel strategies for specific tumour cell targeting are necessary in order to improve survival rates and to reduce side effects of current therapies in cancer patients. Hypoxia is a hallmark of solid tumours and one of the major driving forces for tumour progression. Targeting of the adaptive responses of cancer cells to hypoxia offers opportunities for tumour specific therapies. The aim of this thesis was to study the hypoxic regulation of polyamines and tumour cell-derived microvesicles (MVs), both of which have been associated with tumour development. It was initially demonstrated that epitope-specific interference of cell surface heparan sulphate proteoglycans (HSPGs) by anti-HS antibodies inhibits the bioavailability of exogenous polyamines, and that combined targeting of polyamine biosynthesis by α-difluoromethylornithine (DFMO) and HSPG-dependent uptake by a HIV-1 trans-activator of transcription (TAT) peptide, Tat, results in reduced tumour growth. We found a novel role for the polyamine system in the hypoxia-induced adaptive response of tumour cells; depletion of polyamines sensitizes tumour cells to hypoxic stress and enhances the tumour inhibiting effect of anti-angiogenic therapy. Finally, tumour cell-derived MVs are shown to elicit a hypoxic, pro-angiogenic response in endothelial cells (ECs) and the upregulation of a specific subset of microvesicular proteins and mRNAs by hypoxia implicates MVs as novel biomarkers for hypoxic signalling in cancer cells. This thesis implicates the targeting of hypoxia-induced adaptive responses as a means of obtaining tumour cell specific therapies and suggests the polyamine system and tumour-derived MVs as promising candidates for therapeutic intervention or as biomarkers of cancer disease.