8: Angiogenesis Flashcards
What is the main trigger for angiogenesis?
Hypoxia
What molecules are involved in angiogenesis?
Hypoxia-inducible Transcription factor (HIF)
Regulates gene expression required in angiogenesis
pVHL tumour suppressor gene is bound to HIF and controls its levels by degradation
What happens molecularly in hypoxia?
HIF no longer bound to pVHL
So HIF no longer degraded
HIF goes into nucleus and upregulates genes that promote angiogenesis
What is VEGF?
Vascular Endothelial Growth Factor
Which receptor is a major mediator of VEGF-dependent angiogenesis?
VEGFR-2
What happens during sprouting angiogenesis?
Endothelial TIP cells lead the outgrowth of blood-vessel sprouts towards GRADIENTS OF VEGF.
Tip cell selection is controlled by Notch signalling
Notch receptors have extracellular domain that binds DLL4, and intracellular domain that goes into nucleus and binds to TF
- In stable vasculature, DLL4 and Notch signaling maintain quiescence
- VEGF activation increases expression of DLL4
- DLL4 drives Notch signalling, inhibiting expression of VEGFR2 in adjacent cells. These become Stalk cells.
- DLL4-expressing Tip cells become motile + invasive (sprouting phenotype)
- Stalk cells form the base of the emerging sprout, proliferate to support sprout elongation.
What happens during sprout outgrowth?
Tip cell communicates with ECM and myeloid cells for guidance
What happens during stabilisation/quiescence?
Pericytes bind to outside of sprout and send stabilising signals
There is also barrier formation (cell junctions)
Describe the structure of endothelial cell junctions in sprouts
VE Cadherin allows adhesion between the endothelial cells
Controls contact inhibition - allows formation of a SINGLE layer of cells
What are pericytes?
Mural cells that wrap around the new vessels and produces the stabilising factor Angiopoietin-1
Describe the angiopoietin-Tie2 pathway
Ang-1 binding to Tie2 promotes vessel stability
Ang-2 binding ANTAGONISES Ang-1 (i.e. vessel INstability) and promotes angiogenesis
What diseases would you see an increase in plasma Ang-2?
Heart failure
Sepsis
Chronic Kidney disease
What happens to angiogenesis in tumours
Tumours less than 1mm3 get oxygen/nutrients via diffusion from host vasculature
LARGE tumours (>1mm3) require angiogensis
Tumour secretes angiogenic factors
Newly vascularised tumour no longer relies solely on diffusion (oxygen + nutrients) from host vasculature
Facilitates progressive growth
What is the angiogenic switch?
The point at which the tumour becomes dependent on NEW vasculature
What is the angiogenic switch?
The point at which the tumour becomes dependent on NEW vasculature
How are tumour blood vessels different?
Irregularly shaped Dilated Tortuous Disorganised Leaky/haemorrhagic (excessive VEGF)
Example of drug targeting the VEGF pathway?
Avastin (Bevacizumab) - ANTI-VEGF monoclonal antibody
Side effects?
GI Perforation Hypertension Thrombosis Haemorrhage No overall QOL or survival advantage No overall survival advantage over chemo alone
What are the mechanisms of resistance to anti-angiongenic therapy?
Other angiogenic factors can take over VEGF
Reduced blood supply to tumour means reduced access by chemotherapy drugs
What is vascular mimicry
Tumour cells mimic endothelial cells and form de novo vasculature
What diseases use angiogenic therapy?
ANTI-angiogenic: abnormal retina vascularisation (diabetic retinopathy), Age-related Macular Degeneration (AMD)
Pro-angiogenic: Ischaemic diseases (MI, Peripheral ischaemic disease)
What is Age-related Macular Degeneration and how is it treated?
Main cause of blindness
Abnormal growth of choroidal blood vessels in the eye
‘Leaky’ vessels cause oedema leading to blindness
Anti-VEGF used for treatment
HIGH efficacy unlike for cancer
What is tumor-on-a-chip?
New method for screening anti-angiogenic drugs
Tumours are complex 3D microenvironments
2D in vitro studies do not mimic interaction between tumour cells and extracellular environment. They also lack human vasculature supply
So drug screening with 2D models misleading
In vitro 3D models of cancer have tumour cells in a 3D ECM perfused by human vessels
May improve drug screening
