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By: Carol, Hemi, Sophie and Rebecca
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Physiological process whereby new blood vessels are
formed from pre-existing vessels
It is a normal process seen during embryonicdevelopment, implantation of the placenta andwound healing
However it is also an important process in tumour
malignancy
What is angiogenesis?
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No predetermined genomic plan, lack of genetic
guidance
Depend on cell-cell interactions Cells of vasculature
Non-vascular cells in tumour
Tumour angiogenesis
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= Vascular Endothelial Growth Factor
Production determined by availability of oxygen
Under hypoxic conditions, accumulation of HIF-1and 1VEGF
Ligand of tyrosine kinase receptor (on surface ofendothelial cell)
Proliferation of endothelial cells and re-modelling ofcytoplasm to form walls of capillaries
VEGF
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bFGF (basic fibroblast growth factor)
Binds to receptors on endothelial cells
TGF-
IL-8
Angiopoietin
Angiogenin
PDGF
Other angiogenic factors
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Unclear why tumour vessels are leaky and chaotic
Balance of angiopoietin 1 and 2
Vessel leakiness promotes metastasis
Chaotic vessel formation
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Tumour cells lack angiogenic capability initially
Sudden change pre-neoplastic cells acquire ability
to induce angiogenesis Intense angiogenesis can only begin when cancer
cells become invasive and penetrate the basementmembrane direct contact with stromal cells
Angiogenic Switch
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Wound healing angiogenesis shut down after
normal tissue function restored
Suppression of HIF-1 transcription factorComponents of extracellular matrix Tsp-1, acts on
endothelial cells and stops proliferation
Tsp-1 treatmentproduction of Fas ligand (pro-
apoptotic signal)Agonists of MMPs e.g. TIMPs
Normal suppression of
angiogenesis
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Directed at killing genetically normal cells (stable
phenotype) drug therapies unlikely to become
resistant Inhibiting VEGF slows down tumour growth as well
as preventing further metastasis
Can cause paradoxical response to carcinomas (lead
to higher grade)
Anti-angiogenesis therapies
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Shown to slow down both tumour growth and
angiogenesis
Interfering with RNA prevents production of VEGFreceptors 1 and 2
Anti-VEGF by RNA
interference
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Experimental anti-angiogenesiscauses upregulation of genesassociated with poor survival in
glioblastoma1
Glioblastoma most commonand most aggressive malignantprimary brain tumour in
humans, involving glial cells andaccounting for 52% of allfunctional tissue brain tumourcases and 20% of all intracranialtumours.
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Inhibiting angiogenesis byinhibiting VEGF
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Using siRNA targeting all isoforms of VEGF-A and implanting them in achick chorio-allantoic membrane
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References
1Saidi, A., Javerzat, S., Bellahcne, A., De Vos, J., Bello, L., Castronovo,V., Deprez, M., Loiseau, H., Bikfalvi, A. and Hagedorn, M. (2008),Experimental anti-angiogenesis causes upregulation of genesassociated with poor survival in glioblastoma. Int. J. Cancer, 122: 2187
2198. doi: 10.1002/ijc.23313
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Results
siRNAs specific for VEGF led to a reduction inmRNA levels
- Short term
VEGF siRNA tumours contained no detectableamounts of the protein
VEGF siRNA tumours are avascular
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Angiogenesis= physiological process whereby new bloodvessels are formed from pre-existing vessels
Angiogenic switch
Under hypoxic conditions, accumulation of HIF-1and 1VEGF
-Suppressed in normal cells
Tumor vessels are leaky and chaoticmetastasis
VEGF inhibitionGrowth
Risk of paradoxical response to carcinomas
Exp. anti-angiogenesis causes upreg. of genes assoc. with poorsurvival in glioblastoma
VEGF siRNA tumours are avascularMetastasis
Summary