Vasculature
Chaotic, leaky vessels create pockets of hypoxia, high pressure that collapses capillaries, and easy exits for cancer cells. Normalising rather than destroying them improves drug and immune delivery.
Diagram
Pick a product above a diagram to see the nodes it hits and the escape routes below the block. Hover or tap any node or arrow for what it is; every node opens its target, glossary entry or the pathway page. Violet boxes are druggable targets.
A growing town (tumour) that keeps sending out road-building orders (VEGF). Anti-angiogenic drugs cancel the orders; at the right dose the roads that remain are straighter and better, so police (immune cells) and supplies (drugs) get in.
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.
VHL is the shredder that destroys the 'we are suffocating' memo whenever there is oxygen around. Kidney cancer breaks the shredder, so the memo piles up and the cell keeps ordering new blood vessels and sugar.
What happens
In plain words, then the glossary entries the stage rests on. Chapter 8, The tumour ecosystem: A tumour is a corrupted organ: cancer cells plus the fibroblasts, matrix, vessels, nerves, microbes and immune cells they recruit, and the signals they send to the rest of the body.
Chaotic, leaky vessels create pockets of hypoxia, high pressure that collapses capillaries, and easy exits for cancer cells. Normalising rather than destroying them improves drug and immune delivery.
VEGF angiogenesis. How tumours grow their own blood supply. Low oxygen makes cells release VEGF, which tells blood-vessel cells to sprout toward the tumour.
The angiogenic switch & tumour vessels. 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.
VHL / HIF oxygen sensing. The VHL/HIF pathway is how cells sense oxygen (the 2019 Nobel Prize). VHL destroys HIF when oxygen is present. Kidney cancers lose VHL, so HIF-2α is permanently on and drives blood vessel growth and proliferation.
The molecular players
The proteins and genes at this stage, with their role and how many products act on each. Listed players come from the atlas; drawn players sit as nodes in the diagrams above.
The signal tumours use to grow their own blood supply. Blocking it starves tumours and, surprisingly, helps immunotherapy work.
A master switch that kidney cancer cells leave permanently on when they lose the VHL gene; belzutifan blocks it.
The receptor that macrophages depend on; blocking it shrinks tenosynovial giant cell tumour (a CSF1-driven tumour) and depletes tumour-supporting macrophages, though the latter has not yet helped patients with common cancers.
Where medicines act
Products grouped by the node they hit, most advanced first, with the cancers an approved product is linked to. Pick one above the diagram to see it light up.
- BevacizumabApprovedColorectal cancerOvarian cancerNon-small-cell lung cancer
- AnlotinibApprovedNon-small-cell lung cancerSmall-cell lung cancerSarcomas (soft tissue, bone, GIST)
- AxitinibApprovedRenal cell carcinomaClear cell renal cell carcinomaAdenoid cystic carcinoma
- Bevacizumab (glioblastoma use)ApprovedGlioma & glioblastoma
- CabozantinibApprovedHepatocellular carcinomaAdvanced hepatocellular carcinoma (BCLC C)Renal cell carcinoma
- Camrelizumab + rivoceranibApprovedHepatocellular carcinoma
- DonafenibApprovedHepatocellular carcinomaThyroid cancer
- FruquintinibApprovedColorectal cancer
- +21 more at VEGF / VEGFR →
Open questions
What is not known at this stage: the atlas's own questions, the bottlenecks it bears on, and the ideas in the corpus that try to answer them.
- How do we measure vessel normalisation in patients to time combination therapy?
- Why do anti-angiogenics fail in adjuvant settings?
- early clinicalCAIX theranostics: 89Zr-girentuximab PET and 177Lu/225Ac-girentuximab therapy
Almost every clear-cell kidney cancer carries the CAIX protein. Image it with one radioactive antibody, then treat with the same antibody carrying a therapeutic isotope.
- early clinicalindustryUse a hypoxia scan to pick patients for adenosine-pathway drugs
Tumours starved of oxygen produce a chemical that switches immune cells off. A scan can show which tumours are starved, and those are the ones to treat with blockers.
- early clinicalclinicUse imaging to find the window when tumour blood vessels are working properly
Low doses of anti-blood-vessel drugs briefly make tumour vessels work better, which helps immune cells and other drugs get in. Scans can find that window for each patient.
- early clinicalWhat actually holds T cells at the tumour border?
In immune-excluded tumours T cells reach the border but cannot get in, held back by fibroblasts, matrix, abnormal vessels, CXCL12 gradients or myeloid cells, and TGF-β drugs on their own have failed. If single-cell and spatial profiling can show which stromal programme dominates in each tumour, matching the drug (TGF-β, FAP, CXCR4 or VEGF) to it could let immunotherapy work.
- preclinical evidenceresearchSoften the tissue that new metastases need in order to grow
Cancer cells need stiff, cross-linked tissue scaffolding to settle and grow in a new organ. Blocking the enzymes that build it may stop new colonies taking hold.
Key evidence
Papers in the corpus tied to this stage's pathways, targets and terms, newest first.
- 2025rctHARMONi-2: ivonescimab, a PD-1 x VEGF bispecific, beats pembrolizumab head-to-head in PD-L1-positive lung cancerThe Lancet
- 2021rctCLEAR: lenvatinib plus pembrolizumab versus sunitinib as first treatment for advanced kidney cancerNew England Journal of Medicinechanged practice
- 2020rctIMbrave150: atezolizumab plus bevacizumab replaces sorafenib as first treatment for advanced liver cancerNew England Journal of Medicinechanged practice
- 2019rctPAOLA-1: olaparib added to bevacizumab maintenance in newly diagnosed ovarian cancer, with benefit confined to HRD-positive tumoursNew England Journal of Medicinechanged practice
- 2004rctHurwitz 2004: bevacizumab with chemotherapy for metastatic colorectal cancer, the first anti-angiogenic drug to extend lifeNew England Journal of Medicinechanged practice
- 2003reviewTumorigenesis and the angiogenic switchNature Reviews Cancer
src/data/mechanics-atlas.ts). Players, medicines, escape routes, tests, ideas and papers are resolved from the knowledge graph at build time through the stage's pathways, targets and terms, so every item here has its own page and sources. Where a section is missing, the corpus has no record tied to the stage yet. Nothing here is medical advice; see about and methodology. Stage 8.2 of 56.