Fig. 1. Schematic illustration of the vascular network undergoing sprouting or intussusceptive angiogenesis.

The two mechanism of angiogenesis are not always exclusive, and a tumour can present characteristics of both, especially after anti-angiogenic therapy. On the left the cartoon illustrates how endothelial filaments called sprouts extending into the extravascular space. The accompanying confocal microscope image shows a filamentous bridge between two capillaries across the extracellular space. The endothelial cells and filaments are positive for PECAM-1 (green) and α5β1 integrin (red) in the Rip-Tag2 mouse model of pancreatic cancer. The cartoon on the right magnifies the cylindrical microstructures spanning the lumen of a capillary that are the distinctive feature of intussusception. For reasons not well understood endothelial cells on opposite sides on the lumen start to bulge until they meet to create the intussusceptive pillar. In the scanning electron micrograph on the right, those pillars appear as tiny holes on the outer surface on the vessel. The vascular casts of a colon tumour xenograft model reveal those very characteristic tiny holes of intussusceptive angiogenesis in the larger capillaries. The small diameter of ≈3–5 µm exclude them as mesh-structure in the vasculature. At this point, intussusceptive angiogenesis seems favoured over endothelial cell sprouting in those capillaries.