The tumour microenvironment and angiogenesis Flashcards
How do Stromal cells contribute to tumour growth ?
Growth and survival factors
• Pro-angiogenic factors
• Extra-cellular matrix modifying enzymes that facilitate angiogenesis, invasion and metastasis
What is angiogenesis?
Angiogenesis is the formation of vessels from pre-existing vessels
Describe the process of angiogenesis.
a) One endothelial cell in the vessel wall becomes a tip cell and this creates a new vessel coming out
b) Process that normally occurs in early development where endothelial Pre cursor cells make new vessels and Can occur in tumours – endothelial pre cursol cells can integrate into vessels and differentiate into endothelial cells
c) One capillary can split into two. Pillar formed, which moves outwards and splits one vessel into two. Quick process.
d) Happens in tumours. This is where instead tumour cells making vessels form into the tumour, the tumour cells grow along existing vessels. Major mechanism in how tumour cells get their blood supply.
e) Tumour cells can create channels which allow blood to move into the tumour
Tumour cells can differentiate into cells that look like endothelial cells
What is angiogenesis driven by?
Driven by low oxygen levels (hypoxia).
Tumours have a low oxygen supply
What is HIF-1?
(Hypoxic inducible factor) is a transcription factor and master regulator of oxygen homeostasis
HIF-1 is a transcription factor consisting of two subunits HIF-1a and HIF-1b
• Degradation of the HIF1a subunit is regulated in response to oxygen levels
alpha and beta
Alpha subunit is regulated and beta is expressed all the time
What happens to HIF-1a in HIGHoxygen levels?
In high levels of oxygen a proline hydroxylase enzyme hydroxylates proline residues o HIF-1a
This is recognised and bound by a ubiquitin ligase which catalyses the poly-ubiquitination of HIF-1a
Poly-ubiquitinated HIF-1a is degraded by the proteosome
What happens to HIF-1a in LOW oxygen levels?
In low levels of oxygen there is no longer sufficient oxygen to drive the proline hydroxylation of HIF-1a
HIF-1a associates with HIF-1B and induces transcription of genes required for adaption to hypoxic conditions
A key target of HIF-1 is VEGF
What are the functions of VEGF?
• VEGF-A is the most potent of the VEGF family growth factors at driving angiogenesis
• VEGFR signals via activation of VEGFR-2, a receptor tyrosine kinase
• Dimerisation of VEGFR-2 activates signalling pathways which affect
– Proliferation
– Survival
– Migration
Once activated, signals downstream pathways. Helps promote proliferation. VEGF controls permeability in tight junction cells.
– Vascular permeability
– via modulation of junctional proteins
What is the angiogenic switch?
- There are a number of pro and anti-angiogenic factors
- Angiogenesis occurs when the effects of angiogenic activators are greater than those of the inhibitors
All time balance of pro agiogeneic factors.
Sufficient oxygen, inhibitors far outweigh activators.
Only when low levels of oxygen, Balance tips towards angiogenesis
Describe the stages of sprouting angiogenesis
a) Selection of tip cell
- Loosening of the endothial junction - VEGF signals to cadherin and then they loosen. Allows leakage of plasma proteins (fibrinogen and fibrinectin), these create an extracellular matrix that facilitate angiogenesis
- Endothelial cells also produce proteases that degrade and remodel the matrix
- An endothelial cell specifiy as a tip cell – has finger like projections that sense the environment which guides the new sprout towards the angiogenenic factor
- Grey cells are perocytes which help stabilise small vessels.
b) Stalk elongation and tip guidance
Tip then migrates towards proangiogenic signal (VEGF).
Signalling between tip and cells behind it (stalk cells) which helps maintain their different speificiation.
Then a lumen is formed in the new stalk which attracts perocytes to stabilise the vessels formed.
What does high levels of VEGF do to tumour vessels?
- Tumour growth and hyperplasia of cells from vessels and hypoxia drives VEGF production
- Chronic hypoxia giving rise to high levels of VEGF and inflammatory cytokines create a pro-angiogenic environment
- Vessel formation is abnormal leading to leaky and poorly perfused vessels and persistent hypoxia
What are the inhibition sites of angiogenesis?
- Inhibit production of Angiogenic Factors
- Neutralising antibody
- Soluble receptors which means the antibody mops up the soluble VEGF and prevents it binding to its receptor
- Blocking antibodies that can block angiogenic factor to the receptor
- Small molecule inhibitors that target intracellular tyrosine kinase domain
What is VEGF?
- Induced locally by hypoxia and glucose deprivation
- An endothelial specific growth factor
- Ubiquitously expressed in tumours, local VEGF level is a prognostic marker
- Mainly a stress induced angiogenic factor (important in pathologically induced angiogenesis)
What are the ways to inhibit VEGF?
- Monoclonal antibody to VEGF – Bevacizumab / Avastin
- Soluble receptor – VEGF trap / aflibercept
- Small molecule inhibitors of VEGFR – Sunitinib / sutent, sorafenib / nexavar,
- Antibody blocking binding of VEGF to receptor – IMC 1C11
What can inhibiting VEGF do for tumours?
When you give anti VEGF you reduce the amount of VEGF in the tumour, so tumour cells become more normal (vascular normalization) looking, so more chemotherapeutic drugs targeting the tumour can get in, increased oxygenation and increased radiosensitivity.
