Resistance to Anti-Angiogenic Therapy: Why Tumours Adapt

Switching to Other Angiogenic Factors

When VEGF signalling is blocked, tumours and their stroma often upregulate alternative pro-angiogenic mediators such as FGF2, placental growth factor, angiopoietin-2, and hepatocyte growth factor.

These sustain vessel growth through parallel receptors, which is part of the rationale for multi-target tyrosine-kinase inhibitors and for combinations.

Bypassing Angiogenesis Altogether

Some tumours, particularly in the liver, lung and brain, grow along and around pre-existing host vessels without inducing new ones, a process called vessel co-option. Such tumours are intrinsically less sensitive to anti-VEGF drugs.

Vasculogenic mimicry, where tumour cells themselves form fluid-conducting channels, is another VEGF-independent route.

Recruiting Supportive Cells

Anti-angiogenic pressure and the hypoxia it can cause recruit bone-marrow-derived myeloid cells, tumour-associated macrophages and neutrophils into the tumour. These cells deliver pro-angiogenic and immunosuppressive signals.

Cancer-associated fibroblasts and pericytes also change in ways that support vessel survival and tumour invasion.

Adaptive Tumour-Cell Changes

Reduced perfusion selects for tumour cells that tolerate hypoxia and low nutrients, shifting metabolism and sometimes increasing invasiveness and metastatic spread in preclinical models.

This has raised the question of whether aggressive vessel pruning can, in some contexts, make disease behaviour worse, which is one argument for the vessel-normalisation approach of moderate dosing.

Interpretation Notes

There is no validated molecular test that predicts which tumours will resist anti-angiogenic therapy, so treatment decisions rest on tumour type and trial evidence.

Progression on an anti-VEGF drug reflects biological adaptation rather than a simple on/off resistance mutation, so the concept differs from resistance to targeted kinase inhibitors.

Key Takeaways

• ·Tumours resist anti-VEGF therapy by upregulating alternative angiogenic factors.
• ·Vessel co-option and vasculogenic mimicry bypass new-vessel growth entirely.
• ·Recruited myeloid and stromal cells sustain vessels and suppress immunity.
• ·No molecular predictor of anti-angiogenic resistance is in routine clinical use.