Cancer 8: Angiogenesis Flashcards
What are the different types of disease angiogenesis?
Insufficient
- baldness
- MI (ischaemia) (Important)
- limb fractures
- thrombosis
Vascular malformations
- Angiodysplasia (HHT)
- Cerebral malformations
Excessive
- Retinal disease
- Cancers (important)
- Atherosclerosis
- Obesity
How are blood vessel made?
Vasculogenesis (bone marrow progenitor cell)
Angiogenesis (sprouting) - (important one to learn)
Arteriogenesis (collateral growth
Describe the process of sprouting angiogenesis
1) Lack of oxygen (hypoxia - promotes GF)
2) GF activates endothelial cells
3) endothelial cells undergo conformational change
4) sprout towards the GFs
5) Tip cells (the leader) tells other cells (stalk cells) to stay the same. while it sprouts out.
How is angiogenesis regulated?
It is regulated with a balance of inhibitors and activators
Inhibitors
- Thrombospondin-1
- Statins (angiostatin)
Activators
- VEGFs (vascular endothelial growth factor)
Give one trigger of angiogenesis
Hypoxia is a trigger for angiogenesis
HIF: hypoxia-inducible transcription factor, controls regulation of gene expression by oxygen. In the absence of oxygen it transcribes VEGF.
pVHL: Von Hippel Lindau tumour suppressor gene, controls the levels of HIF. In the presence of oxygen HIF is bound to pVHL which inhibits HIF.
What are the members of the VEGF family?
VEGF-A VEGF-B VEGF-C VEGF-D PlGF (placental growth factor)
What receptors to VEGF bind to?
Tyrosine kinase receptors:
VEGF receptor: Three types - VEGF receptor 1,2 and 3.
2 co-receptors: Nrp1 and Nrp2
Describe VEGFR-2
It is the major mediator of VEGF-dependent angiogenesis, activating signalling pathways that regulate endothelial cell migration, survival and proliferation.
What specialised cells are involved in sprouting angiogenesis?
In sprouting angiogenesis, specialised endothelial tip cells lead the outgrowth of blood-vessel sprouts towards gradients of VEGF.
The tip cell moves towards the VEGF gradient. Not every cell becomes a Tip cell this is controlled by notch signalling.
What is the canonical notch signalling pathway
Notch receptors and ligands are membrane-bound proteins that associate through their extracellular domains.
The intracellular domain of Notch (NICD) translocates to the nucleus and binds to the transcription factor RBP-J
The notch receptor would be on the stalk cell while the ligand is on the tip cell.
Describe selection of Tip cells: VEGF/Notch signalling
1) In stable blood vessels, Dll4 and Notch signaling maintain quiescence
2) VEGF activation increases expression of Dll4
3) Dll4 drives Notch signalling, which inhibits expression of VEGFR2 in the adjacent cell. One cell just decides to be the tip cell
4) Dll4-expressing tip cells acquire a motile, invasive and sprouting phenotype
5) Adjacent cells (Stalk cells) form the base of the emerging sprout, proliferate to support sprout elongation.
What happen during sprout outgrowth?
Stalk elongation
Tip guidance
stabilisation and quiescence
What is Ve-cadherin?
- Constitutively expressed at junctions
- Mediates adhesion between endothelial cells
- Controls contact inhibition of cell growth - promotes single layer of cells.
- Promotes survival of EC
What cells stabilise the neovessels?
Mural cells - pericytes produce the stabilzing factor angiopoietin-1
What is the angiopoietin-Tie2 pathway?
Ang-1 and Ang-2 are antagonistic ligands of the Tie2 receptor
Ang-1 binding to Tie2 promotes vessel stability and inhibits inflammatory gene expression
Ang-2 antagonises Ang-1 signalling, promotes vascular instability and VEGF-dependent angiogenesis
What diseases have raised Ang-2 plasma levels?
congestive heart failure
sepsis
chonic kidney disease
Summarise sprouting angiogenesis?
Initiation
Selection (of tip cells)
Tip-cell navigation
Stalk elongation
Describe the progression of tumour angiogenesis and neovasculature?
Tumors less than 1 mm3 receive oxygen and nutrients by diffusion from host vasculature.
Larger tumors require new vessel network. Tumor secretes angiogenic factors that stimulate migration, proliferation, and neovessel formation by endothelial cells in adjacent established vessels.
Newly vascularized tumor no longer relies solely on diffusion from host vasculature, facilitating progressive growth.
What is the angiogenic switch?
The angiogenic switch is a discrete step in tumour development that can occur at different stages in the tumour-progression pathway, depending on the nature of the tumour and its microenvironment
The point where the tumour depends on a new set of vessels to grow.
Describe tumour blood vessels?
- irregularly shaped, dilated, tortuous
- not organized into definitive venules, arterioles and capillaries
- leaky and haemorrhagic, partly due to excessive VEGF
- perivascular cells are often loosely associated
- some tumours may recruit endothelial progenitor cells from the bone marrow (controversial!)
What agents target the VEGF pathway?
Anti-VEGF antibodies (MAb) - Avastin
What are the side effects of avastin?
GI perforation Hypertension Proteinuria Venous thrombosis Haemorrhage Wound healing complications
No overall survival advantage over chemo alone
No quality-of-life or survival advantage
Does anti-angiogenic therapy in cancer work?
- In some cases benefits are transitory, and followed by a restoration of tumour growth and progression
- In other cases there is no objective benefit
- Two modes of unconventional resistance:
1) evasive resistance, an adaptation to circumvent the specific angiogenic blockade
2) intrinsic or pre-existing indifference
What are the challenges with finding therapeutic strategies to inhibit angiogenesis in cancer?
See slides
Describe angiogenic therapy in other diseases?
Anti-angiogenic therapies for abnormal retina vascularization (diabetic retinopathy, wet AMD)
Pro-angiogenic therapies for ischemic diseases (myocardial infarction, peripheral ischemic disease)
What is age-related macular degeneration (AMD)
Abnormal growth of choroidal vessels
- Leaky vessels cause oedema
- Visual impairment
Lucentis - used to treat AMD. Pretty much the same molecular structure of avastin
Describe the therapeutic use of angiogenesis for CHD and peripheral artery disease?
Promote neo-vascularisation to prevent ischemic damage
