Angiogenesis Flashcards
What are the three ways of making blood vessels?
Vasculogenesis – formation of new blood vessels from bone marrow progenitor cells
Angiogensis – formation of new blood vessels by sprouting from pre-existing vessels
Arteriogenesis – collateral growth of blood vessels that is dependent on shear stress and external factors like macrophages
What is the main signal for angiogenesis?
Hypoxia
What is the most important pro-angiogenic factor?
VEGF (Vascular Endothelial Growth Factor)
Explain the mechanism by which hypoxia triggers angiogenesis.
HIF (hypoxia-inducible factor) is a transcription factor that is responsible for the expression of genes involved in angiogenesis
In normoxic conditions, HIF is bound to von Hippel Lindau protein- pVHL (tumour suppressor), which inhibits HIF from promoting angiogenesis
In hypoxic conditions, HIF is not bound to von Hippel Lindau so it can regulate transcription and express genes involved in angiogenesis
How many members are there in the VEGF family? List them.
5
VEGF-A, B, C, D
PIGF (placental growth factor)
How many tyrosine kinase receptors are there for VEGF? List them.
3
VEGFR 1, 2 and 3
How many coreceptors are there for VEGF? List them.
2 Neuropilin 1 (Nrp 1) and 2
Which receptor is the major mediator in VEGF-dependent angiogenesis?
VEGFR2
What pathway is crucial for the selection of tip cells?
Notch signalling
What happens when the notch ligand binds to the notch receptor?
The intracellular NICD domain is cleaved
This then translocates to the nucleus and binds to the transcription factor RBP-J and regulates transcription
What is another name for the notch ligand?
Delta-like ligand (Dll4)
What effect does VEGF have on notch signalling?
VEGF activation increases expression of Dll4
Dll4 drives Notch signalling, which inhibits expression of VEGFR2 in the adjacent cell
Dll4-expressing tip cells acquire a motile, invasive and sprouting phenotype
Adjacent cells (Stalk cells) form the base of the emerging sprout, proliferate to support sprout elongation.
Which cell type is involved in vessel anastomosis and helping stabilise newly formed vessels by promoting tip cell fusion?
Macrophages
Which other cell type is recruited to help with the stabilisation of the newly formed vessel?
Pericytes
Which cell adhesion molecules are essential for vessel stabilisation and quiescence?
Name some of its functions
VE-Cadherin
- expressed at junctions
- maintains adhesion between endothelial cells
- controls contact inhibition of cell growth
- promotes survival of EC
What growth factor do pericytes produce that is important for stabilisation of new blood vessels?
Angiopoietin 1
Which important signalling pathway modulates the activation and return to quiescence of endothelial cells?
Angiopoietin-Tie2 signalling pathway
Describe the actions of angiopoietin 1.
Ang-1 binding to Tie2 promotes vessel stability and inhibits inflammatory gene expression
Describe the actions of angiopoietin 2.
Ang-2 antagonises Ang-1 signalling, promotes vascular instability and VEGF-dependent angiogenesis
What is the name given to the point at which a tumour begins to initiate signals to generate new vasculature?
Angiogenic switch
What are some of the issues with tumour blood vessels?
They are not properly formed because the signals are not physiological
- Vessels can be irregularly shaped, distended, tortuous
- Not organised intro arteries, capillaries, veins
- Perivascular cells loosely associated
- Leaky and haemorrhagic partly due to excess VEGF
Haemorrhage is common in tumours. - some tumours may recruit endothelial progenitor cells from the bone marrow (controversial!)
What is the aim of anti-angiogenic therapy in cancer?
To normalise tumour blood vessels to reduce hypoxia and improve efficiency of drug delivery
What are the consequences of being too aggressive with anti-angiogenic therapy?
This can make the tumour blood supply inadequate for the delivery of drugs
What is avastin?
Anti-VEGF humanised mouse antibody
Also called bevacizumab
What are the side effects of avastin?
GI perforation Hypertension Proteinuria Venous thrombosis Haemorrhage
What are the two main methods of unconventional resistance to VEGF blockade?
Tumour adopts evasive strategy – adapts to bypass the angiogenic blockade
Intrinsic or pre-existing difference – a tumour may not have been particularly sensitive to VEGF in the first place
What did avastin start getting used for other than cancer?
Age-related macular degeneration (AMD)
What slightly modified form of avastin became licensed by the FDA to treat AMD?
Lucentis (ranibizumab)
When would you get increased ANG-2 levels?
Congestive heart failure
Sepsis
Chronic Kidney Disease
What receptor do both Ang 1 and Ang 2 antagonise?
Tie2 receptor
Ang-1 and Ang-2 are antagonistic ligands of the Tie2 receptor
Name some classes of agents that target the VEGF pathway
- Anti- VEGF antibodies
- Soluble VEGF receptors
- Anti- VEGF antibodies
- Small molecule VEGFR inhibitors
Give an example of a Soluble VEGF receptor?
VEGF- Trap
Give an example of a anti VEGF antibody
IMC-1121b
Give examples of small molecule VEGFR inhibitors
Vatalnib
Sunitinib
How can anti-angiogenic therapy sometimes facilitate effects that seem pro-tumour growth? What are we aiming for>
- sustained anti0angiogenic therapy can lead to too much ischaemia and thus release of hypoxic factors that further induce angiogenesis
- vasculature may become refractory to treatment
- vasculature may be inadequate fo further delivery of oxygen/drugs
aiming for
- reduces hypoxia so less hypoxic factors
- increases efficacy of conventional therapies
