Angiogenesis denotes the growth and remodelling process of the nascent primitive network into a complex network involving sprouting and bridging from pre-existing vessels, while arteriogenesis refers to the stabilisation of these sprouts by mural cells. During embryonic development, blood vessels are formed by vasculogenesis and angiogenesis, while new vessels in adults mainly arise through angiogenesis, although vasculogenesis by bone marrow-derived endothelial progenitors also may occur.^1,2

In 1971, Judah Folkman first described the fundamental points of tumour angiogenesis:³ most primary solid tumours go through a prolonged state of avascular growth in which the maximum size attainable is 1–2mm in diameter. Up to this size, simple passive diffusion enables tumour cells to obtain the necessary oxygen and nutrient supplies that they require for growth and survival. However, beyond this diffusion limit, tumours need to switch on angiogenesis by recruiting and inducing surrounding mature host blood vessels to sprout new capillaries that grow towards and finally infiltrate the tumour mass, thus enabling the expansion of the tumour itself and haematogeneous metastatic spread.⁴ Therefore, inhibiting tumour growth by blocking tumour angiogenesis represents a therapeutic approach that is not curative in the usual sense as it would not eradicate all tumour cells, but would, instead, either prevent any new expansion of tumour mass or cause sustained regression of established solid tumours to a size where survival is possible without any blood supply.⁵ Physiological vessel growth differs greatly from vessels arising in cancer.¹ Tumour vessels are structurally and functionally abnormal, as well as tortuous and enlarged with uneven diameter. They also have excessive brunching and shunts. Due to numerous openings (endothelial fenestrae, vesicles and trans-cellular holes), widened inter-endothelial junctions and a discontinuous or absent basement membrane, tumour vessels are also leaky.⁶ In addition, they often lack protective mechanisms that normal vessels acquire during maturation. For example, tumour vessels lack an organised coat of perivascular cells that normally protect against vessel regression and provide vessels with necessary vasoactive control.^7,8 Consequently, blood flow in tumour vessels is chaotic, slow and not sufficient in meeting metabolic demands,⁹ leading to hypoxic and acidic regions in tumours, conditions that may lower the efficacy of anti-cancer treatments.^9,10 Hence, normalisation of the chaotic tumour vasculature by angiogenic inhibitors may facilitate intra-tumoural drug delivery.¹¹