1. Why Is Angiogenesis Needed Flashcards
What is the role of the blood?
Provides oxygen and nutrients
Removes (metabolic) waste products eg metabolic acid
What is VEGF
Vascular endothelium growth factor.
It induces angiogenesis
Which cancers can bevacizumab be used to treat?
Cancers of the:
- Colorectal
- Lung
- Kidney
- Brain
What does CB31 stain?
Blood vessels (endothelium)
What does bevacizumab do?
Reduces tumour vascularisation
Describe the outcome of tumour vascularization of samples treated with and without bevacizumab
Tumours continue to grow in both samples.
There is more necrosis in ample treated with bevacizumab due to targeting VEGF, decreasing vascularization.
Briefly explain what happens in a tissue leading up to tumour angiogenesis
- Tumour cells grow along pre-existing blood vessels
- Increased tumour growth leads to hypoxia and necrosis. The tumour outgrows the blood supply.
- Angiogenic sprouting is initiated. Hypoxia induces the expression of kinochines which induce angiogenesis
What is the diffusion distance of oxygen in tumour tissue?
80-100 um
How do tumour cells contribute to hypoxia in the tissues it invades?
- The tumour cells have high metabolic
- Uncontrolled growth of tumour cells
At what distance from blood vessels is necrosis observed in tumour cells
> 180um (O2 has diffusion distance of 80-100um)
Which markers are used to observe:
A) hypoxia
B) blood vessels
A) EF5
B) PECAM/CP31
What is HIF
Hypoxia inducible factors
What does low levels of O2 lead to? (Proteins in angiogenesis)
Stabilization of HIF1a and HIF2a
Briefly describe how HIFs behave in hypoxic conditions
- HIF1a and HIF2a are stabilized, under normal conditions they are constantly degraded.
- They regulate the expression of pro-angiogenic proteins
- When stabilized, they heterodimerise with HIF1/2B (ARNT)
- They bind to HRE (HIF response element) sequence in DNA, to then regulate genes involved in many aspects of hallmarks of cancer (proliferation, metabolis, metastasis, angiogenesis, etc)
Describe 3 proteins and their processes which are increased in response to angiogenesis
- VEGF - production leads to auto rinse signals for angiogenesis
- MMPs - frees pro-angiogenic factors from the stroma
- Angiopoietin-2 - increases vascular basement membrane degradation & endothelial cell migration
What cells are MMPs released from?
Hypoxic tumour cells & VEGF-activated endothelial cells
Briefly outline the process of angiogenesis
- VEGF stimulates increased vasodilation & permeability of blood vessels
- ANG2 signalling reduces vascular pericyte coverage
- VEGF & ANG2 induce release of MMPs (matrix metalloproteinases) which degrade the ECM (extracellular matrix)
- Endothelial tip cells migrate towards stimuli
- Stalk cells follow migrating tip cells
- Stalk cells proliferate to form vascular lumen in response to activity of integrins (Cdc42 and Rac)
- Blood vessels may also be co-opted by tumours which grow along vessels
What are MMPS
Matrix metalloproteinases
They degrade the ECM
Explain how hypoxic tumours are radiotherapy resistant
Free radicals cannot be formed or fixed as the process requires O2.
Hypoxia is the absence of O2, so damage cannot be induced, and radiotherapy is not effective.
What are the 3 reasons hypoxic tumours are chemo resistant?
- Supply
- Flux
- Consumption
Explain how hypoxic tumours are chemo resistant via supply
- Supply of a drug > tissue depends on dose and pharmacokinetics
- With limited vasculature supplying tumour tissue, drugs cannot be delivered to kill tumour cells
Explain how hypoxic tumours are resistant to chemo via Flux
- Movement is hindered by interactions with extracellular and cellular components, and the barrier posed by cell membrane.
- Factors include: molecular weight/ size of drug, the charge of drug, and water/lipid solubility of drug through membrane
Explain how hypoxic tumours are resistant to chemo via consumption
- cellular metabolism will reduce drug penetration and build up.
- Binding and sequestration can increase net tissue levels of a drug but limit penetration
Describe how a hypoxic tumour’s method of metabolism affects resistance to chemo.
A shift in metabolic pathways from oxidative to glycolysis can alter the flux of various biochemical reactions within cells.
