As solid tumours enlarge, diffusion limits create regions of hypoxia and nutrient stress. Many tumours respond by increasing pro-angiogenic signals, recruiting and remodelling blood vessels, or co-opting existing vasculature. The 'angiogenic switch' describes a shift toward vessel-promoting activity, but vascular biology varies across tumour types. VEGF- and VEGFR-directed drugs are incorporated into selected labelled regimens rather than representing one universal standard across cancer.
Tumour hypoxia — inevitable as rapidly dividing cells outgrow their oxygen supply — stabilises HIF-1α by inhibiting the PHD enzymes that normally tag it for VHL-mediated proteasomal degradation. Stabilised HIF-1α drives VEGFA transcription from its HRE-containing promoter. Secreted VEGFA165 binds VEGFR2 on adjacent endothelial cells, activating PLCγ/PKC (endothelial proliferation), PI3K/AKT (survival), and SRC/FAK (permeability and migration) cascades. Together these drive tip cell specification, stalk cell proliferation, and lumen formation — creating new vascular conduits that relieve hypoxia and supply nutrients for further tumour growth.
Tumour hypoxia — inevitable as rapidly dividing cells outgrow their oxygen supply — stabilises HIF-1α by inhibiting the PHD enzymes that normally tag it for VHL-mediated proteasomal degradation. Stabilised HIF-1α drives VEGFA transcription from its HRE-containing promoter. Secreted VEGFA165 binds VEGFR2 on adjacent endothelial cells, activating PLCγ/PKC (endothelial proliferation), PI3K/AKT (survival), and SRC/FAK (permeability and migration) cascades. Together these drive tip cell specification, stalk cell proliferation, and lumen formation — creating new vascular conduits that relieve hypoxia and supply nutrients for further tumour growth.
Rapidly dividing tumour cells create hypoxic pockets (<1% O2). Hypoxia inhibits PHD enzymes (which require O2 for catalysis), preventing Pro402/564 hydroxylation of HIF-1α. Without hydroxylation, VHL cannot ubiquitinate HIF-1α — it stabilises, accumulates, and translocates to the nucleus.
Secreted VEGFA165 binds VEGFR2 (KDR) extracellular domains, inducing receptor homodimerisation and autophosphorylation at Tyr1054/1059 (activation loop) and Tyr1175 (PLCγ/Shb docking). VEGFR1 (FLT1) acts primarily as a decoy to fine-tune VEGFA bioavailability.
High VEGFA gradients preferentially activate DLL4/Notch signalling in leading endothelial 'tip cells', which extend filopodia guided by VEGFA gradients. DLL4-Notch in tip cells suppresses VEGFR2 expression in neighbouring 'stalk cells', enforcing tip/stalk hierarchy to ensure directional and controlled vessel sprouting.
VEGFR2-mediated SRC activation loosens VE-cadherin adherens junctions (vascular permeability), enabling endothelial cell migration. Stalk cells proliferate to extend the sprout behind the tip. Lumen formation occurs through cell hollowing or cord hollowing mechanisms. PDGFB secreted by endothelial cells recruits pericytes for vessel stabilisation.
Biallelic VHL loss in clear cell renal cell carcinoma prevents normal oxygen-dependent degradation of HIF-α subunits, sustaining a hypoxia-like transcriptional programme in normoxia. HIF-2α is particularly important in this disease. The resulting vascular dependence helps explain the activity of HIF-2α-, VEGF- and VEGFR-directed strategies, but response is not uniform and depends on the regimen and disease setting.
Angiogenesis is a near-universal requirement for solid tumour growth beyond micrometastasis. Tumour vasculature is structurally aberrant — tortuous, leaky, poorly perfused — creating the hypoxia that drives further VEGF production (positive feedback). Bevacizumab-containing regimens improve overall survival in colorectal cancer (bevacizumab + FOLFOX/FOLFIRI) and progression-free survival in ovarian cancer, NSCLC, and cervical cancer.
Bevacizumab (anti-VEGFA monoclonal antibody) normalises tumour vasculature, improving drug delivery and reducing oedema (particularly in GBM). VEGFR TKIs (sunitinib, pazopanib, axitinib, cabozantinib) target intracellular VEGFR signalling and are approved for RCC, HCC, and thyroid cancer. Belzutifan (HIF-2α inhibitor) is approved for VHL disease-associated tumours. Resistance mechanisms include FGF2, PDGF, angiopoietin-2 as VEGF-independent angiogenic signals.
What is the angiogenic switch?
The angiogenic switch is the transition from an avascular to a vascularised tumour state, defined by an imbalance between pro-angiogenic (VEGFA, FGF2, angiopoietins) and anti-angiogenic (thrombospondin-1, endostatin, angiostatin) signals tipping in favour of neovascularisation. It typically occurs at tumour sizes of 1–2 mm and marks a key transition in tumour progression toward metastatic competence.
Why does anti-VEGF therapy fail over time?
Resistance to anti-VEGF therapy arises through multiple mechanisms: upregulation of alternative angiogenic factors (FGF2, PDGF, angiopoietin-1/2, EGF) that drive angiogenesis independent of VEGFA; vessel co-option (tumours grow along pre-existing vessels without neoangiogenesis); increased pericyte coverage making vessels less VEGFA-dependent; and selection of hypoxia-tolerant tumour cell populations.
How tumour hypoxia stabilises HIF-1α to drive VEGFA transcription, how VEGFA activates the VEGFR2 signalling cascade for vessel sprouting, and how bevacizumab and VEGFR TKIs block this angiogenic pathway.
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