carcinogenesis 5: angiogenesis Flashcards
what is angiogenesis?
the formation of new blood vessels
what are the physiological bases for angiogenesis?
- development
- menstrual cycle
- wound healing
what are the pathological bases for angiogenesis?
- cancer
- chronic inflammatory disease
- retinopathies
- ischaemic disease
what are the 3 stages of blood vessel formation?
- vasculogenesis - mobilisation of endothelial progenitor cells (from bone marrow)
- angiogenesis - sprouting of new capillaries from existing ones
- arteriogenesis - collateral growth
what is VEGF?
vascular endothelial growth factor
- family of cytokines -A -B -C -D & PIGF (placental growth factor)
- acts through tyrosine kinase-linked receptors VEGFR-1 -2 or -3 (with coreceptors Nrp1 & Nrp2)
how does VEGF work?
binds to cell -> cell becomes tip cell -> instructs adjacent cells to become stalk cells
what are the activators for angiogenesis?
VEGF family v important
growth factors: VEGF/FGF families, TGFβ, PDGF
soluble factors: IL-6, FXIII, TNF-α
cell surface receptors: av β3
what are the inhibitors of angiogenesis?
ECM: thrombospondin-1, angiostatin, endostatin
soluble factors: VEGF-R, IL-10, IL-12, TNFα
cell surface receptors: avβ3
what happens during sprouting angiogenesis?
- VEGF gradient leads to tip cell selection
- tip cell navigation & stalk cell proliferation due to notch signalling
- branching coordination using macrophages & myeloid cells
- stalk elongation, tip cell fusion & lumen formation
- perfusion & vessel maturation
how does hypoxia affect angiogenesis?
it triggers angiogenesis
what factors are involved in hypoxic stimulation of angiogenesis?
HIF (hypoxia inducible transcription factor - controls regulation of gene expression) pVHL (Von Hippel-Lindau TSG - controls levels of HIF using hydroxyproline)
- in oxygen pVHL donates hydroxyproline to HIF-α -> destruction
- in hypoxia pVHL lacks hydroxyproline -> binds HIF -> binds to hypoxia inducible genes eg VEGF to cause angiogenesis
what are the 5 stages of notch signalling?
- VEGF causes cells to become tip cells -> expression of Notch ligand (DII4)
- DII4 binds to Notch receptors on adjacent cells (interactions via extracellular domains)
- Notch signalling in adjacent cells downregulates VEGFRs to prevent stalk cells becoming tip cells
- intracellular domains of notch receptors translocate to nucleus and bind to RBP-J transcription factors to increase stalk cell phenotype
- stalk cells acquire a motile, invasive and sprouting phenotype to push the tip cell towards thee VEGF gradient
what happens in sprout outgrowth?
sprouts grow towards each other
what role do macrophages play in angiogenesis?
support sprouting & promote tip cell fusion
- carve tunnels in ECM to provide channels for capillary infiltration
- tissue-resident macrophages can be associated with angiogenic tip cells
what role do platelets play in angiogenesis?
modulate angiogenesis -contain pro- and anti-angiogenic factors
what happens during stabilisation?
junctions form between endothelial cells using VE-cadherin with homophilic interaction mediating adhesion between cells
what do pericytes do?
cover cells - closely related to VSMCs and wrap around vesselgs - use angiopoietin/Tie2 system to modulate vessels
- Ang-1: agonistic ligand to Tie-2 receptor -> promotes vessel stability and inibits inflammatory gene expression
- Ang-2: antagonisitic to Ang-1 -> promotes vascular instability & VEGF dependent angiogenesis
how are tumour blood vessels architecturally different from normal vessels?
- irregularly shaped, dilated & twisted
- not organised into definitive arterioles, capillaries & venules
- leaky & haemorrhagic, with perivascular cells more loosely associated
what sized tumours require new blood vessels?
> 1mm^3
what is the angiogenic switch?
discrete step in tumour devlopment that can occur at different stages based on the nature of the tumour and its microenvironment
- hypoxia leads to factor production to drive neovessel formation (eg Ang-1/2 & VEGF)
what do fibroblasts do in tumour angiogenesis?
fibroblasts: secrete ECM & pro-angiogenic factors eg VEGF / FGF
what do pericytes do in tumour angiogenesis?
loosely associated with tumour vessels, favour chronic leakage enhanced by angiopoietin 2
what do platelets do in tumour angiogenesis?
release pro-angiogenic mediators & proteases that support proliferation - link between cancer progression & thrombocytosis
what are the different ways in which angiogenesis can be controlled?
- inhibition of ECM breakdown
- inhibition of signal transduction
- inhibition of endothelial cell function
- blocking activators of angiogenesis
- antagonising receptors
- damaging existing tumour vasculature
what is endostatin?
endogous inhibitor of angiogenesis
- additional endostatin can be given to cancer patients to slow growth of cancer
what is anti-VEGF threrapy?
monoclonal antibodies gainst VEGF as well as receptor blockers and VEGFR kinase inhibitors
- block pathways -> reduce tumour growth
what is avastin?
anti-VEGF humanised mAb used for tumours eg colorectal
- however no overall survival advantage over chemo / QOL benefits + side effects such as HTN, GI perforation, proteinuria, thrombosis & haemorrhage
how can tumours develop resistance to anti-VEGF therapy?
VEGF inhibition aggravates hypoxia -> increased production of other factors
- tumour vessels less sensitive to inhibition than regular cells - tumour cells recruiting pericytes may be less responsive
- vascular mimicry: tumour cells mimic vessels
why does tumour vasculature need to be normalised not eliminated?
chemotherapy needs to reach tumour
what is AMD and how can it be treated?
age-related macular degeneration - abnormal growth of choroidal blood vessels -> leaky vessels cause oedema & visual impairment
- use anti-VEGF therapy to treat
