Tumour Angiogenesis

During its avascular stage a tumour is small enough to take in nutrients and to expel waste by diffusion. However diffusion is not sufficient to support any continued growth of the tumour. This is because the tumour consumes nutrients at a rate proportional to its volume whereas the supply of nutrients is delivered at a rate proportional to its surface area. The avascular tumour can sometimes become dormant and there is an indefinite period for which growth stops.

The tumour can overcome this deficiency by acquiring a blood supply and it does so by inducing neighbouring blood vessels to grow towards the tumour (angiogenesis). The tumour releases angiogenic factors (or TAF) which diffuse into the surrounding tissue. The first reaction to this stimulus is that the endothelial cells (EC) in the neighbouring vessels and nearest to the chemical source start to alter their structure.

Figure showing endothelial cells

Stimulated by the TAF the EC begin to migrate. The EC accumulate in the region where the concentration of angiogenic factors has first reached a threshold level. The vessel wall begins to bulge as EC pile up to form sprouts. The capillary sprouts begin to grow in length by recruiting EC from the parent vessel. At some distance from the tip of the sprout EC begin to proliferate. The EC in the outgrowing sprouts start to reassociate with each other. The development of intracellular lumen, where vacuoles appear within the EC, and intercellular lumen, where vacuoles appear between the outgrowing sprouts, leads to the formation of tube-like structures. Branches form in a similar way whereby an intracellular vacuole becomes Y or T shaped before fusing with the primary lumen.

Figure showing endothelial cells within capillary sprout

Initially the sprouts are parallel with each other vessel but tend towards each other as they elongate. Neighbouring sprouts will eventually fuse together at their tips to form loops (anastomoses). This signals the beginning of circulation of blood. It is essential that there is a flow of blood through the tumour since an effective system for transporting waste products away from the tumour is vital. As the vessels mature, the EC resynthesize a basal lamina in order to restore continuity. The looped vessels may bud or loops may fuse with other loops until a complex network of vessels develop. Finally this network penetrates the tumour, providing it with the circulatory system and the supply of nutrients that it requires for growth.

Figure showing vascularized tumour penetrated by capillaries

In order to support continued growth the tumour's vascular system persistently remodels itself. Hence angiogenesis is an on-going process, continuing indefinitely until the tumour is removed or killed, or until the host dies. J. Folkman and colleagues have suggested that anti-angiogenesis could prove effective in the treatment of cancer.