Angiogenesis Flashcards
(37 cards)
What is angiogenesis?
Formation of new blood vessels from existing blood vessels.
In a healthy adult where/when can angiogenesis be seen?
Wound repair and the female reproductive cycle.
Describe an avascular tumour.
This is a tumour before angiogenesis has begun. Avascular tumours are slow growing and exist as a bundle of cells 10^5 to 10^6 cells.They can not grow further until they become vascularised.
Neovascularised tumours (after angiogenesis) show what kind of growth?
Expedential growth which can be 1cm^3 plus.
How can tumours be graded with respect to angiogenesis?
By their microvessel count (MVC).
What are direct angiogenic factors?
Factors what stimulate endothelial cell proliferation in vitro.
Give some examples of direct angiogenic factors.
VEGF (vascular endothelial growth factor), FGF (fibroblast growth factor), PD-EGF (platelet-derived endothelial growth factor).
What is VEGF (vascular endothelial growth factor)?
A direct angiogenic factor which stimulates endothelial cell growth and increases permeability.
What is fibroblast growth factor (FGF)?
A direct angiogenic factor which stimulates endothelial cell proliferation and differentiation.
What is platelet-derived endothelial growth factor (PD-EGF)?
A direct angiogenic factor which stimulates endothelial cell proliferation and the recruitment of smooth muscle.
What are indirect angiogenic factors?
Other cofactors to stimulate endothelial cell proliferation.
Give some indirect angiogenic factors.
Epidermal growth factor, transforming growth factor (extracellular matrix) (TGF-alpha and -beta), tumour necrosis factor (TNF-alpha), prostaglandins, HETE.
What are inhibitors of angiogenesis?
Factors that stop endothelial cell division.
Give come inhibitors of angiogenesis.
Angiostatin, endostatin, retinoic acid, tissue inhibitors of metalloproteinases (TIMP-1 & -2).
Describe the angiogenic process.
An avascular tumour needs angiogenesis to grow further.
The tumour produces angiogenic factors such as VEGF and bFGF.
Host capillaries prodice matrix metalloproteinases (MMPs).
ENdothelial cells grow towards the tumour.
Oxygen and nutrients can then reach the tumour and the tumour begins to grow rapidly.
This can then lead to metastasis.
What are matrix metalloproteinases?
Zinc containing enzymes which break down the extracellular matrix and tissues, allowing the endothelial cells to grow towards the tumour.
Outline the process of metastasis.
Tumour cells leave the primary tumour site and invade local host tissue. Tumour cells then enter circulation and eventually arrest at a distant vascular bed. They then extravate into the target organ tissue and proliferate as a secondary colony.
How many anti-angiogenic drugs are in developmenr, in clinical trials, or have FDA approval?
> 300.
What are the three main classes of anti-angiogenic drugs?
Blocking growth factors, blocking intracellular signalling, blocking intercellular signalling.
Give an example of anti-angiogenic drugs which block growth factors.
Bevacizumab (avastin), itraconazole.
Give an example of anti-angiogenic drugs which block intracellular signalling.
Tyrosine kinase inhibitors e.g. sunitinib (Sutent) and IFN-alpha.
Give an example of anti-angiogenic drugs which block intercellular signalling.
Thalidomide.
What are some other targets for anti-angiogenic drugs?
Other targets include basement membrane degradation (MMP inhibitors), migration inhibitors (endostatin) and immune stimulators (CM101).
How does SU11248 (Sunitinib) work?
It is a VEGF-R2 receptor antagonist which prevents the autophosphorylation of the receptor.
