Tumour Angiogenesis: How Cancers Build a Blood Supply

The Angiogenic Switch

Small tumours can persist without their own vessels, relying on diffusion. Growth beyond roughly one to two millimetres creates hypoxia and nutrient limitation, tipping the balance of pro- and anti-angiogenic factors toward vessel growth.

This transition, the angiogenic switch, is considered a discrete step in tumour progression and is driven substantially by HIF-mediated VEGFA induction.

Sprouting Angiogenesis

In the best-characterised route, a VEGF gradient selects a tip cell that leads a new sprout, while neighbouring stalk cells proliferate behind it. Notch signalling between endothelial cells enforces the tip-versus-stalk decision.

New sprouts connect to form loops, lumens open, and pericytes are recruited to stabilise the vessel. In tumours this process is chaotic and never fully completes.

Non-Sprouting and Alternative Routes

Vessels can also expand by intussusception, where an existing vessel splits in two, and tumours can incorporate bone-marrow-derived cells or recruit existing host vessels by co-option.

Some tumours form channels lined by tumour cells rather than endothelium, called vasculogenic mimicry. These alternative routes are less dependent on VEGF and contribute to resistance against anti-VEGF drugs.

Why Tumour Vessels Are Abnormal

Tumour vasculature is leaky, tortuous, unevenly perfused and poorly covered by pericytes. This raises interstitial pressure, creates hypoxic pockets and impairs delivery of drugs and immune cells.

The vessel-normalisation hypothesis proposes that carefully dosed anti-angiogenic therapy can transiently make vessels more normal, improving perfusion and the effect of chemotherapy or immunotherapy given alongside.

Therapeutic Implications

Anti-angiogenic drugs are established in several cancers but rarely curative alone, and tumours adapt by upregulating alternative pro-angiogenic factors or switching to VEGF-independent vascularisation.

Combinations with immunotherapy are an active area, based partly on the idea that improving the vasculature also improves immune-cell access.

Key Takeaways

• ·The angiogenic switch is a discrete step driven largely by hypoxia and VEGFA.
• ·Sprouting angiogenesis uses a tip/stalk decision controlled by Notch.
• ·Tumours also use intussusception, vessel co-option and vasculogenic mimicry.
• ·Abnormal tumour vessels impair drug and immune-cell delivery, motivating normalisation strategies.