Angiogenesis 2 Flashcards

1
Q

Give an overview of the process of new blood vessel formation.

6 marks

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is Notch signalling and its mechanism?

4 marks

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Outline the process of how cells are induced to be either stalk or tip cells with VEGF.

6 marks

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are some characteristics of tip cells?

2 marks

A
  • Selected by high VEGF exposure - migratory shows little proliferation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What are some characterisitcs of stalk cells?

2 marks

A
  • Low VEGFR-2 levels due to Notch actiation
  • Proliferate and elongate
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What do sprouting vessels do with other ‘sprouts’?
1 mark

A

Join up together to form continuous vessles and new vasculature rapidly matures - includes pericyre recruitment

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What are the new sprouting cells of a tumour involved in?

1 mark

A

Producing PDGF-B signales to pericytes to stabilise vessel

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

How do tumour cells promote angiogenesis through stromal cells?
2 marks

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What are BMCs?

1 mark

A

Progenitor cells that can differentiate into endothelial cells - activated as well in tumour angiogenesis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

How can you target VEGF ligand?

3 marks for process

3 marks for drugs

A
  • 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 well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

How can you target VEGF receptor?

1 mark

A

VEGFR antibodies i.e. block ligand binding site on receptor so VEGF can’t bind

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What are some of the direct affects of VEGF ligands binding inhibition?

5 marks

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What is one downside to VEGF ligans inhibition?

1 mark

A
  • Treatment must be continuous to prevent tumour growth
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

How is VEGFR signalling blocked?

1 mark

A

Small molecule tyrosine kinase inhibitors - competitive inhibitors of ATP binding site in TRK e.g. sorafenib, sunitinib & axtinib

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Explain the specificity difference between axtinib and sorafenib.

2 marks

A

Axtinib: selective for VEGFR but can affect PDGFR and Kit

Sorafenib: inhibits both VEGR and PDGFR

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

How did axitinib activity affect thyroid and advanced pancreatic cancer when combined with chemotherapy?

2 marks

A
  • Axitinib shows anti-cancer activity in advanced thyroid cancer - selective for VEGFR inhibitor
  • Almost ineffective in advanced pancreatic cancer
17
Q

What does inhibition of PDGFR activity promote?

1 mark

A

Dissociation of pericytes from endothelium and enhances sensitivity to other anti-angiogenic therapies

18
Q

How can resistance to anti-angiogenic pathways be supported by proteins other than VEGF? How can they be targeted?

2 marks

A

Through FGF and PDGFR pathways

Dovitinib is meant to target VEGF, FGF & PDGFR

19
Q

ACTIVE RECALL ON EXTRA READING SLIDE

A