Angiogenesis 2 Flashcards
Give an overview of the process of new blood vessel formation.
6 marks
- Pericytes detatch themselves from basement membrane and destabilises vessel
- Endothelial cells loosen junctions between each other and blood vessels more leaky allowing for permeabilty and extravasion of plasma proteins
- Plasma proteins providing provisional matrix for sprout to travel along endothelial cell known as tip cell is selected to lead migration to source of VEGF
- Signalling ensures tip cell only migrates and doesn’t divide and is covered in filopodiea to help it move
- Beside tip cells have stalk cells that follow along behind tip cell to esure it only proliferates and elongates and not migrates
- Tip cell forms by responding to gradient of VEGF secreted by VEGFR-2
What is Notch signalling and its mechanism?
4 marks
- Acts as a transmembrane receptor
- Binds to ligands which causes irreversible proteolytic cleavage of notch
- This makes notch release cytoplasmic protion which can act as TF
- 4 isoforms form 4 different genes - known as ‘dual address’ protein as can be both receptor and transcription factor
Outline the process of how cells are induced to be either stalk or tip cells with VEGF.
6 marks
- Endothelial cell closest to VEGF gradient selected to be the tip cell
- Tip cell develops filopodia
- Filopodia lots of VEGFR2 allows them to sense and line up with VEGF gradient
- Sufficient filopodia anchored to substratum, active filament in filopodia will retract and pull tip cell along substratum
- Active filament in filopodia retracts and pull tip cell along
- VEGF dampens mirgatory region of stalk cells make sure they proliferate and not migrate as well
What are some characteristics of tip cells?
2 marks
- Selected by high VEGF exposure - migratory shows little proliferation
What are some characterisitcs of stalk cells?
2 marks
- Low VEGFR-2 levels due to Notch actiation
- Proliferate and elongate
What do sprouting vessels do with other ‘sprouts’?
1 mark
Join up together to form continuous vessles and new vasculature rapidly matures - includes pericyre recruitment
What are the new sprouting cells of a tumour involved in?
1 mark
Producing PDGF-B signales to pericytes to stabilise vessel
How do tumour cells promote angiogenesis through stromal cells?
2 marks
- Tumour vessels stimulate stromal cells to make more GF to perpetuate angiogenesis
- Stromal cells also producing ligands for growth factors like MET and other GF
What are BMCs?
1 mark
Progenitor cells that can differentiate into endothelial cells - activated as well in tumour angiogenesis
How can you target VEGF ligand?
3 marks for process
3 marks for drugs
- Monoclonal antibodies e.g. bevacizumab and ranibizumab (bind VEGF-A165)
- Aptamers e.g. pegatanib (VEGF-A110)
- Chimaeric soluble receptors e.g. VEGF-trap (combo domains from VEGFR-1/2 multiple VEGFs)
How can you target VEGF receptor?
1 mark
VEGFR antibodies i.e. block ligand binding site on receptor so VEGF can’t bind
What are some of the direct affects of VEGF ligands binding inhibition?
5 marks
- Regression of new tumour vasculature, which is associated with:
- Reduced tumour growth
- Decreased metastatic potential
- Regression of existing tumour vasculature, which is linked with:
- Reduced tumour volume and weight
What is one downside to VEGF ligans inhibition?
1 mark
- Treatment must be continuous to prevent tumour growth
How is VEGFR signalling blocked?
1 mark
Small molecule tyrosine kinase inhibitors - competitive inhibitors of ATP binding site in TRK e.g. sorafenib, sunitinib & axtinib
Explain the specificity difference between axtinib and sorafenib.
2 marks
Axtinib: selective for VEGFR but can affect PDGFR and Kit
Sorafenib: inhibits both VEGR and PDGFR
