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25 Cards in this Set
- Front
- Back
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What is the role of Angiogenesis? |
To from new blood vessels from pre-existing vasculature. |
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Where is angiogenesis important? |
1. Wound healing 2. Ovulation 3. Menstruation 4. Retinopathy 5. Cancer |
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How does a small tumour receive nutrients? |
By diffusion from a quiescent vessel. |
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What activates the angiogenic switch? |
VEFG- A, B and C FGF1 and 2 |
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What inhibit the angionenic switch? |
Thromobspondin 1 and 2 Interfereon alpha and beta Angiostatin Endostatin Collagen 4 fragments
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What is the organisation of blood vessels in a tumour? |
Disorganised |
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What is tumour cell viability governed by? |
range of 02 diffusion.
as distance from the vessel increases o2 concentration increases |
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What happens to the blood vessel density as a tumour grows? |
Blood vessel density increases |
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What enhances disease-free survival probability in patients with low blood vessel density? |
Low blood vessel density |
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What does anti-angiogenic therapy comprise of? |
Killing the blood vessels and thus killing the tumour |
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Describe the cellular changes that occur to sprout angiogenesis: |
-Soluble factors activate endothelial cells -Endothelial proliferation induces sprout formation -Endothelial cells migrate and form tubes that invade into the tumour mass. |
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What is a key feautre of tumour blood vessels? |
They are leaky |
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What molecular changes occur to sprout angiogenesis? |
< 15 growth factors are released - VEGF and PDGF.
Enhanced growth factor receptor expression occurs
Enhanced MMP and integrin expression on endothelial cells. (MMP9) |
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Describe the synthesis and action of VEGF: |
Made by stromal and tumour cells Usually tethered to the ECM. In tumours, macrophages produce MMPs mobilising VEGF to stimulate angiogenesis.
Stimulates angiogenesis |
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Describe the synthesis and role of PDGF: |
It is produced by endothelial cells Usually tethered to the endothelial BM Involved in pericyte recruitment
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What is the main driver of VEGF production? |
Hypoxia |
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Name 2 VEGF- co-receptors: |
Neuropilin 1 and Neuropilin 2 |
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What are intergrins? |
Extracellular matrix receptors.
Heterodimeric transmembrane glycoproteins. Consist of one alpha and one beta subunit. |
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Give some examples of specific integrins and what they bind: |
Alpha5Beta1 - binds fibronectin Alpha11bBeta3 - binds fibrinogen
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How do some intergrins inteact with the ECM? |
By binding to RGD |
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What is an alternative name for MMP-1 and MMP-2? |
Collagenase-1 Gelatinase-A |
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What are the problems with anti-angiogenic drugs? |
Dose choices- upper limit dosing Drugs have varied effects on different tumours. Fast and slow growing tumours have different angiogenic requirments Assessed by effect on tumour shrinkage. Molecular crosstalk/cross-regulation means tumours out smart anti-angiogenic therapy = some antagonsists can acts as agonsits.
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Give an example of molecular cross talking: |
Low dose integrin antagonist enhances VEGF-R2 levels ---> enhances angiogenesis |
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What effect does combination therapy have? |
It prevents regression - affects pericytes and endothelial cells. |
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What is the role of pericytes and how can they be useful targets in anti-angiogenic |
Pericytes provide protective survival functions to endothelial cells. Their presence increases the endothelial cell's resistance to VEGF-R and makes the cells less sensitive to chemo.
Targetting pericytes via PDGF receptor inhibitiors results in impaired support and protection by pericytes.
Endothelial cells become very sensitive to VEGF-R inhibition and chemotherapy.
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