Angiogenesis Cancer SGT

8/13/2019 Angiogenesis Cancer SGT

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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

Documents

Angiogenesis Cancer SGT