Novel Regulators of Tumour Angiogenesis

Abstract

The work in this thesis describes two novel inhibitors of tumour angiogenesis, both of which target the vasculature. One is a first-in-class oligonucleotide-based inhibitor (Blockmir CD5-2) that normalises tumour angiogenic vessels, the other, an endogenously expressed gene (ARHGAP18) that is essential for the stabilisation of blood vessels. CD5-2 is an oligonucleotide based drug that inhibits the binding of miR-27a to a specific target in endothelial cells, VE-cadherin, resulting in a modest increase in its expression. CD5-2 administration to tumour bearing mice induces structural and functional normalisation of tumour vasculature and results in retardation of tumour growth likely through enhanced distribution of CD8+ T cells within the tumour parenchyma, and increased tumour cell apoptosis. The strength of the effects of CD5-2 in vivo are postulated to lead to significant and broad range of downstream pathways activated as a result of enhancing the expression of VE-Cadherin. ARHGAP18, a member of the RhoGTPase family, acts as a negative regulator of vessel generation and maturation in endothelial cells. However, in tumour cells ARHGAP18 has opposite effects where overexpression results in promotion of proliferation and migration. Thus, ARHGAP18 may impact tumour growth through its action on two of the major compartments.