Lec 20- Angiogenesis Flashcards
1
Q
Tumour growth requires angiogenesis
A
- Avascular (before angiogenesis) slow growing and exist as a bundle of cells 105 to 106 cells
- No further tumour growth until they become vascularised- due to lack of nutrients
- Neovascularized (After angiogenesis)= expediential growth which can be 1 cm3 plus -
- Tumours can be graded by their microvessel count (MVC)
- In a 15 yr breast cancer study, survival rates in patients with low MVC were 92% irrespective of tumour size
- The greater the number of blood vessels the worse the prognosis- indicates how important angiogenesis is to the cancer
2
Q
Endothelial cells
A
- These cells have a high potential for cell division which is tightly controlled
- There are direct and indirect angiogenic factors
- There are also potent angiogenic inhibitors
- We need to promote endothelial growth through angiogenic factors
3
Q
Direct angiogenic factors
A
- Stimulate endothelial cell proliferation in vitro
- VEGF- vascular endothelial growth factor (permeability)
- FGF- Fibroblast growth factor (Acidic and basic)- proliferation and differentiation endothelial cells
- PD-EGF- platelet-derived endothelial cells growth factors (recruit smooth muscle cells)- Stimulate the growth of endothelial cells
- Acts at receptor tyrosine kinases to initiate there action
4
Q
Indirect angiogenic factors
A
- Other co-facrosto stimulate endothelial cell proliferation- but also other processes
- EGF- epidermal growth factor
- TGF-a and b- transforming growth factor (Extracellulatmatrix)
- TNF-a tumour necrosis factor
- Prostaglandins and HETE
5
Q
Inhibitors of angiogenesis
A
- Stop endothelial cell division
- Angiostatin, endostatin, retinoic acid
- Tissue inhibitors of metalloproteinases TIMP-1+2
6
Q
Angiogenic process
A
- Firstly tumours are running out of nutrients as they grow in size known as avascular tumour (with nearby blood vessels)
- When they sense there running out of nutrients the tumour release angiogenic factors (VEGF, bFGF)
- Capillaries produce Matrix Metalloproteinases (MMPs)- break down the structures of cells between the blood vessels and cancer to make room for the blood vessel to get closer
- Zn containing enzymes that breakdown the tissues
- Endothelial cells to grow towards the tumour
- Canalisation and branching, typical irregular tumour vascular
- The rapid growth of vascularized tumour
- Oxygen + nutrients
- => TUMOUR CELLS => metastasis
- Now that tumour is in direct contact with the vasculature, the tumour can invade the blood vessels- they can start to release tumour cells (circulating tumour cells CTC’s). These get lodged someone else in the body (usually with fine vasculatures such as kidney or liver) and new cancer can form this is known as metastasis’- V.poor prognosis
7
Q
A
8
Q
Metastasis
A
- Tumour cell(s) leave primary tumour site
- Matrix metalloproteinases (MMPs)- critical role
- Not only help in angiogenesis but also allow tumour cells to enter vasculature, allow the tumour to invade local tissue, important in the growth of secondary tumours
- Matrix metalloproteinases (MMPs)- critical role
- Invade local host tissue
- ANGIOGENESIS- MMOs
- Enter circulation arrest at a distant vascular bed
- MMPs
- Extraverted into the target organ tissue
- MMP
- Proliferate as secondary colony = Angiogenesis
9
Q
Anti-angiogenic drugs
A
- >300 drugs in development, on clinical trial or with FDA approval
- 3 main classes
- Blocking growth factors- e.g. bevacizumab (Avastatin) intraconazole
- Block intracellular signalling- tyrosine kinase inhibitors e.g. sunitinib, IFN-a
- Block intracellular signalling e.g. thalidomide
- Other targets include basement membrane degradation (MMP inhibitors), migration inhibitors (endostatin) and immune stimulators (CM101)
10
Q
A
11
Q
Drugs that inhibit angiogenesis directly
A
12
Q
SU11248
A
- VEGF-R2 receptor antagonist (and PDGF, KIT)- prevents autophosphorylation of receptors
- Tyrosine kinase inhibitor
- Inhibits TK that EGF binds to so prevents the signal for proliferation being received by cell
- Stops phosphorylation of the receptor
- Lots of the drugs used
- The further up the kinase pathway the less we have to inhibit- amplification pathway
- Well tolerated
- Stable disease observed with lung, colo-rectal and renal cancers
- Approved for renal cell carcinoma
- Side effects- HTN, Fatigue, Diarrhoea, acral erythema
- Side effects reversible- you can take a couple of days of without serious effect (side effects leave realtively quickly)
13
Q
Angiostatin
A
- Control angiogenesis within the body
- An internal fragment of plasminogen approximatley38 kDa
- Inhibits endothelial cell proliferation
- Well tolerated
- High efficacy
- In Phase III clinical trial
- This is a large molecule (protein)- don’t follow Lipinski so can’t penetrate membranes
14
Q
Endostatin
A
- Controls angiogenesis within the body
- 20kDa fragment of c-terminus of collagen XVII
- Blocks mitogen activated protein kinase (MAPK) in endothelial cell proliferation
- 30 times more potent than angiostatin
- Phase I clinical trial few side effect and tolerated well, now in phase III
- Patients with sarcoma, melanoma and neuroendocrine tumours
15
Q
Avastin
A
- Bevacizumab- anti-VEGF mAb
- Sequesters VEGF preventing receptor activation- preventing angiogenesis and pathway can’t be activated
- The first clinically approved angiogenic inhibitor
- Colo-rectal, lung, breast (outside the USA), Glioblastoma (the USA only), kidney and ovarian
- Side effects may include heightened risk bleeding hypertension exacerbation CAD and other artery disease
- This is actually killing the tumour (through lack of nutrients) rather than most which cause the tumour to become static
