ANGIOGENESIS NOTES
BI3325: CANCER BIOLOGY:ADVANCES IN MECHANISMS AND TECHNIQUES
Activators & Inhibitors
Angiogenesis (AG): is the formation of new blood vessels by ‘sprouting’, regulating step in tumour growth,
leaky vasculature enables escape of cancer cells into blood allowing metastasis
Blood vessel histology: 3 layers: endothelium(EC), pericyte (undifferentiated) & basement membrane
Normal AG: embryogenesis; by endothelial precursor cells, sprouting from blood plexus network. Adulthood:
growth, female reproductive cycle & wound healing. Stable processes
Abnormal AG: destabilisation of blood vessels, tumourigenic process, unstable and dynamic
Tumour vasculature: irregularly shaped BCs, pericytes=loosely attached, fail to stabilise as lack of pericyte
attachment, dilated/no hierarchy, lack organisation due to ↑ endothelial GF. ↓ effectiveness of chemo
Activation of AG: switched on at any point in tumour life-cycle, 2 phases: avascular; dormant, no AG, no
clinical symptoms, should you treat? and vascular; activation of AG, tumour growth and spread
Processes in AG: 1. Avascular lesion contains dividng cancer cells next to BV, 2. Tumour turns on
AG and BV becomes destable, 3. Facilitates sprouting into tissue, 4. BV try to stabilise by
recruiting pericytes but not as good as normal BVs, 5. Process continues as tumour grows.
AG activators: VEGFs, VEGFRs, FGF, FGFR, angiopoietin, TIE, angiogenin, MMPs, androgens,
oestrogens, integrins etc.
AG inhibitors: thrombospondin 1&2, angiostatin, endostatin, vasostatin, tumstatin, canstatin,
interferons, interleukins, proteolytic fragments
Statins : are cryptic inhibitors. Angiostatin; produced by plasminogen cleavage by MMPs
inhibits prolif and migration of ECs. Endostatin;fragment of collagen XVIII, binds to integrins
inhibiting them and MAPK altering migration and division. Thrombospondin; inhibits cell
migration and proliferation= therapeutic target
HIF-1 in angiogenesis
Hypoxia: regulates AG through HIF, made of HIF-1a and HIF-1B subunits, regulated at HIF-1a by O2 &
VHL
Regulation of HIF-1a: Normoxic; o2 activates prolyl4 hydroxylase which modifies prolines on HIF-
1a, VHL binds to hydroxylated proline promoting ubiquitinylation and degradation of HIF-1a by
proteosomal pathway. Hypoxic: P4H not activated & HIF-1a forms TF which binds to HIF response
elements (AG inducers e.g. VEGF)
Von-Hippel-Lindau syndrome (VHL): defects in tumour suppressor VHL results in haemangioblastmoas
HIF-1a as TT: as alpha= regulatory subunit most drugs target this, through HIF-1a transcription, translation,
DNA binding and protein degradation. HIF overexpression=poor prognosis
HIF-1a inhibitor: RX-0047 reduces HIF-1a mRNA and protein expression in various cell lines, compared to
control RX-0047 treatment ↓ A459 lung tumour xenograft after 3 weeks
VEGF and VEGFRs in Angiogenesis
VEGF: produced throughout tumour life cycle, genetically stable and not susceptible to
mutation, VEGF-A can generate abnormal blood vessels. 4 VEGF ligands & 3 receptors, neuropilin=receptors.
VEGF-A: ligand, several splice variants exist, overexpressed in tumour cells, variant 165 is crucial to AG
VEGF-A types: 121=freely diffusible ∴ long range. 165:free &ECM bound ∴ short & long range. 189=heparin
sulphate and ECM bound ∴ short range. ECM bound forms can be cleaved by plasmin and MMPs= active
soluble. Some tumours require release of bound ligand for AG e.g. VEGF-A in Rip-Tag pancreatic tumour
VEGF-B,C,D & PLGF: B; coronary artery dev. C/D; lymphangiogenesis. PLGF; placental GF, ↑ in tumours
VEGFR: VEGF1;TK activated by VEGF-A, decoy receptor for VEGF-A as low activity, ↑ in tumours, PLGF can
bind with stronger affinity ∴ ↑ VEGF-A to bind to VEGFR-2 so more AG. VEGFR-2: TK weakly binds to VEGF-
A, ↑ in tumours. Neuropilins; no TK activity, present VEGF-A enhancing VEGFR2 activation
