**2. The role of VEGF in tumour angiogenesis**

Angiogenesis is considered to be a fundamental event in tumour progression and metastatic dissemination and is [2] regulated by numerous endogenous factors that stimulate or inhibit neovascularisation [3]. One of the most studied pathways is the vascular endothelial growth factor (VEGF) family of ligands and their receptors [5]. In humans and mice, the VEGF family consists of 5 members: VEGF-A, -B, -C, -D and placental growth factor (PIGF). These ligands demonstrate variable specificity for the three VEGF receptors (VEGFR1, VEGFR2, VEGFR3) [3, 5]. The predominant member of the VEGF family involved in tumourigenesis is VEGF-A and will be referred to as simply 'VEGF' from herein.

One of the most important stimuli for tumour angiogenesis is hypoxia, which can occur when a rapidly growing tumour exceeds the ability of the local vasculature to supply its needs. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor, made up of two DNA binding proteins (HIF-1α and HIF-1β), which induces the transcription of many genes, including VEGF [6]. In the presence of adequate oxygen concentrations, HIF-1α is ubiquitinated and subsequently degraded by the proteasome. However, under hypoxic conditions, HIF-1α is stabilised and persistently dimerises with the other subunit, HIF-1β, to form the HIF-1 heterodimer. The stabilised HIF-1 is then able to bind the VEGF promoter, leading to persistent transcription of the VEGF gene [7]. The expression of VEGF is also stimulated by oncogenes, including Ras, c-Src, Bcr-Abl and p53 [8]. A multitude of studies have shown that VEGF is overexpressed in the majority of solid tumours and that it is a key driver of sprouting angiogenesis [9]. Furthermore, it has been demonstrated in multiple xenograft models that VEGF inhibition supresses tumour growth [10].
