Cancer 8 - Angiogenesis Flashcards
Give 3 examples of physiological angiogenesis
- Embryonic development
- Wound healing
- Menstrual cycle
What can insufficient angiogenesis cause?
Baldness
Ischaemia/MI
Limb fractures
Thrombosis
What can vascular malformations (improper angiogenesis) cause
Angiodysplasia (HHT + VWD), cerebral malformations (AVM/CCM)
What can excessive angiogenesis cause?
Retinal disease, cancers, atherosclerosis, obesity
Name a pro-angiogensesis stimulus
VEGF - causes activated cell to change polarity + cytoskeleton which drives vessel sprouting —- forming TIP cell
What do adjacent cells to the tip cell do?
Divide to stabilise the new vessel
How is a balance of angiogenesis maintained
Balance between inhibitors and activators ensured
What are the triggers for angiogenesis
Hypoxia - mediated by
- HIF –> Hypoxia Inducible TF (controls regulation of gene expression by oxygen)
- pVHL –> Von Hippel-Lindau TSG, controls HIF levels
Explain how pVHL interacts with HIF
If sufficient oxygen - pVHL binds HIF - causing ubiquitination in HIF –> HIF degraded
If insufficient oxygen –> pVHL doesn’t bind HIF –> more HIF enters nucleus and binds HIF-beta —> drives transcription of genes promoting angiogenesis
How many members are in the VEGF family
5
VEGF A/B/C/D
Placental Growth Factor (PIGF)
What type of receptors bind the VEGF family and how many are there?
What is the coreceptor?
3 tyrosine kinase receptors - different dimer combinations
Co receptor is neuropilin 1/2
Which is the major VEGFR that mediates VEGF-dependent angiogenesis
VEGFR2 - activates signal pathways that regulate endothelial cell migration, survival, proliferation
Endothelial tip cells lead outgrowth of blood-vessel sprouts towards what gradient?
VEGF gradient
How is it determined which endothelial cell becomes the tip cell?
Notch signalling
How does a notch receptor and ligand bind
Notch receptor (stalk cell) and ligand (delta-ligand-4 on tip cell) are both membrane bound proteins —> they associate via extracellular domains
What happens when the notch ligand binds the receptor
Intracellular domain (NICD) gets cleaved and translocates to the nucleus –> binds to TF RBP-J
Explain how VEGF/notch signalling helps select the tip cells
- DII4 and notch signalling stable in quiescent cells –> because signalling on both cells
- VEGF activation - increased DII4 expression
- Cell with more DII4 expression becomes the tip - DII4 expression drives notch signalling - inhibiting VEGFR2 expression in adjacent cell
- The DII4 expressing tip cells acquire motile, invasive, sprouting phenotype
- Adjacent cells form base of emerging sprout and proliferate to support sprout elongation
Which 2 things are involved in sprout outgrowth?
- Cytoskeletal reorganisation
2. Myeloid cell recruitment (e.g. in retina can help process)
What is the role of VE-cadherin in sprouting angiogenesis
- Constitutively expressed at junctions
- Mediates adhesion between endothelial cells
- Controls contact inhibition of cell growth
- Promotes survival of endothelial cell
What type of cancer can arise from loss of cadherin control
Epithelial cancers
How do mural cells (e.g. pericytes) help stabilise me-vessels?
Pericytes normally wrap around capillaries - also produce Angiopoietin-1 (stabilising factor)
Ang1 and Ang2 both bind to the Tie2 receptor. Explain their antagonistic effects
Ang1/Tie2 = vessel stability + anti-inflammatory gene expression
Ang2/Tie2 = antagonises Ang1 signalling, promotes vascular instability and VEGF dependent angiogenesis
Which Ang is released more in inflammation as it helps the inflammatory response?
Ang2
Plasma Ang2 is raised in disease. Name some diseases in which it is higher
- Congestive heart failure
- Sepsis
- CKD
What is Vascular Permeabiltiy Factor?
Same as VEGF
What is avastin?
Anti-VEGF monoclonal antibody - used for advanced colorectal cancer but turned out to be ineffective
Small tumours (<1 mm3) survive from oxygen and nutrients received how?
Via diffusion from host vasculature
How do larger tumours survive?
They secrete angiogenic factors - creates a new vessel network that stimulates migration, proliferation + be-vessel formation by endothelial cels (in existing adjacent cells)
What is the angiogenic switch
The point in the growth of a tumour where it now depends on angiogenesis for growth
5 features of tumour blood vessels
- Loss of balance of angiogenesis factors
- Irregularly shaped, dilated, tortuous and fragile —> meaning rupture-prone
- Not organised well into venues, arterioles, capillaries
- Leaky + haemorrhage (due to excessive VEGF)
Give an example of an anti-VEGF humanised monoclonal antibody
Avastin (bevacizumab)
typically used in advanced stages of cancer
What is Avastin used for in first line treatment of metastatic colorectal carcinoma?
Avastin + 5-fluorouracil
What are the side effects of using Avastin in cancer therapy?
No overall survival advantage over chemo alone
GI perforation Hypertension Proteinuria Venous thrombosis Haemorrhage Wound healing complications
What are the 2 modes of resistance to anti-angiogenic cancer therapy
- Evasive resistance = adaptation to circumvent specific angiogenic blockade
- Intrinsic/pre-existing indifference = if tumour more dependent on different GFs
Give 6 cancers that bevacizumab (Avastin) may be used to treat
- Cervical
- Colorectal
- Glioblastoma
- Non-small cell lung cancer
- Ovarian epithelial, Fallopian tube / primary peritoneal cancer
- Renal cell cancer
What are 2 ways to feed a tumour?
- Angiogenesis - tumour secrete factors which stimulates vessel growth –> vessel grows into tumour
- Tumour cell vasculogenic/vascular mimicry –> plasticity of aggressive cancer cells forming de novo vascular networks –> associated with malignant phenotype and poor prognosis
What is the solution to the 2D in vitro tumour modelling problem currently being faced?
“Tumour on a chip” - in vitro disease model with vasculature also
Give an example of antiangiogenic therapy in other diseases?
Abnormal retina vascularisation (e.g. diabetic retinopathy/ wet AMD)
What causes age related macular degeneration
Abnormal growth of choroidal blood vessels —> leaky vessels cause oedema causing visual impairment
What is the main cause of blindness?
AMD
How can therapeutic angiogenesis be used for coronary artery disease and PAD
Promote neovascularisation - to prevent ischaemic damage
e.g. induce neo-angiogenesis in ischaemic myocardium using human GFs (may require proteins, stem cells, gene therapy)
