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A tumour cannot grow beyond a couple of millimetres without its own blood supply. The 'switch' flips when the signals calling for new vessels (VEGF, FGF, angiopoietin) outweigh the ones holding them back (thrombospondin). The vessels that result are leaky and chaotic, which starves the tumour of oxygen, blocks drugs, and gives cancer cells a way out.
Hypoxia (HIF), oncogenes (RAS, MYC), p53 loss (which normally induces thrombospondin-1) and inflammatory cells tip the balance of pro-angiogenic (VEGF-A/C, FGF2, PDGF-B, ANG2, PlGF) over anti-angiogenic (TSP-1, endostatin, angiostatin) factors. Endothelial tip cells (VEGFR2, DLL4-Notch selection) sprout, stalk cells proliferate, pericytes (PDGFRβ) stabilise; ANG2 destabilises. Alternatives: vessel co-option (liver, lung, brain metastases; a mechanism of bevacizumab resistance), intussusception, vasculogenic mimicry, and bone-marrow-derived endothelial progenitors. Tumour vessels are tortuous, leaky, poorly pericyte-covered and lack hierarchy, producing heterogeneous hypoxia, acidity, high interstitial pressure (which collapses vessels further and blocks drug penetration), and easy intravasation. Anti-VEGF therapy at moderate doses 'normalises' vessels transiently, improving perfusion, drug delivery and T-cell entry, the basis of IO-VEGF combinations. Resistance: alternative ligands (FGF, ANG2, PlGF), myeloid cells, co-option, and increased invasiveness.
A new housing estate demanding roads. Once the developers (VEGF) outvote the planners (thrombospondin), roads are laid overnight: badly, with dead ends and potholes, so deliveries (oxygen, drugs) fail and the estate's residents can slip out onto the motorway. Anti-VEGF drugs do not close the roads; used well they make the few that remain drivable.
Shares Hypoxia-activated prodrugs, CSF1R, VHL / HIF oxygen sensing, HIF-2α and the tags mechanism, mechanics-atlas.
Shares CSF1R, VHL / HIF oxygen sensing, HIF-2α, Intravasation & circulating tumour cells and the tags mechanism, mechanics-atlas.
Shares CSF1R, Myeloid suppression: TAMs, MDSCs & don't-eat-me signals, Tumour microenvironment (TME), Ivonescimab and the tags mechanism, mechanics-atlas.
Shares CSF1R, Myeloid suppression: TAMs, MDSCs & don't-eat-me signals, PD-1 and the tags mechanism, mechanics-atlas.
Shares VHL / HIF oxygen sensing, HIF-2α, Belzutifan and the tags mechanism, mechanics-atlas.
Shares Renal cell carcinoma, PD-1, Glioma & glioblastoma and the tags mechanism, mechanics-atlas.
Shares Microenvironment and inflammation: tumours as wounds that do not heal, Tumour microenvironment (TME), PD-1, Colorectal cancer and the tags mechanism, mechanics-atlas.
Shares VEGF angiogenesis, Ivonescimab, VEGF / VEGFR, PD-1 and the tags mechanism, mechanics-atlas.