Blood vessels arose during evolution carrying oxygen and nutrients to distant organs via complex networks of blood vessels penetrating organs and tissues. Mammalian cells require oxygen and nutrients for survival, of which oxygen has a diffusion limit of 100 to 200？μm between cell and blood vessel. For growth beyond this margin, cells must recruit new blood vessels, first by vasculogenesis, where embryonic vessels form from endothelial precursors, then angiogenesis which is the sprouting of interstitial tissue columns into the lumen of preexisting blood vessels. Angiogenesis occurs in many inflammatory diseases and in many malignant disease states, including over 90% of solid tumours. Malignant melanoma (MM) is the most lethal skin cancer, highly angiogenic, highly metastatic, and refractory to all treatments. Raised serum levels of vascular endothelial growth factor (VEGF) strongly correlate MM disease progression and poor prognosis. Melanoma cells secrete several proangiogenic cytokines including VEGF-A, fibroblast growth factor (FGF-2), platelet growth factor (PGF-1), interleukin-8 (IL-8), and transforming growth factor (TGF-1) that modulate the angiogenic switch, changing expression levels during tumour transition from radial to invasive vertical and then metastatic growth. We highlight modern and historical lines of research and development that are driving this exciting area of research currently. 1. Angiogenesis Angiogenesis was first associated with malignancy 100 years ago [1] being new vessel growth from a pre-existing blood supply. It is physiologically tightly regulated during wound healing, embryogenesis, and female reproduction. It also occurs in several pathological conditions including malignant melanoma. In 1919, Krogh described a tissue cylinder surrounding an axial blood vessel allowing oxygen and glucose diffusion for metabolism [2]. In 1945, vascularised tumour cell transplants used in vivo murine models survived to promote tumour survival and growth [3]. A diffusible “angiogenic” substance was later proposed in 1968 using a hamster cheek pouch model demonstrating choriocarcinoma vasoproliferation [4]. In 1971, Folkman postulated that tumour growth and metastasis driven by angiogenesis might be blocked by inhibiting angiogenesis (6). Later it was recognised, ischaemic stress occurs as the tumour growth exceeds the distances of Krogh’s cylinder, resulting in ischaemic necrosis, or ischaemic/hypoxic induced activation of angiogenesis [5] with diffusion limits of oxygen for cell survival measured at 100–200 microns [6]. Beyond this
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