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ANGIOGENESIS


Angiogenesis at the Tissue Level:
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Small tumours, i
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the size of a grain of rice, are capable of growing and surviving
within the already-formed blood vessels
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However, once they grow beyond 1-2mm3, they begin to starve due to the lack of
oxygen and nutrients
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Inhibitors of this switch include:
- Angiostatin
- Endostatin
- Collagen IV fragments




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- Furthermore, the larger the tumour becomes, the more likely it will metastasis
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Tumour vessels are very distinct in comparison to normal vessels
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Normal vasculature have:
- A very uniformed layer
- Tight junctions between the cells
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Whereas the tumour vessels have:
- Endothelial cells that have grown on top of each other,
- Bridges,
- Protrusions,
- Abnormal cell connections
- Leakiness (a major characteristic of tumour vessels)
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In a normal vessel, pericyte’s (express SMA, smooth muscle actin) sit in tight
proximity to the blood vessel, but in tissue vessels, these cells are not as closely
related to the vessels, and can in fact be described as “hanging on for dear life”
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Pericyte’s stabilise the vessel and this does not occur correctly in cancer
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Overall: the role of perciyte’s include:
- Communicate survival signals to endothelial cells
- Help in endothelial cell angiogenic remodelling
- Help regulate capillary blood flow as they are contractile
- Help sustain the blood brain barrier


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The tumour cells exploit and migrate into the lymphatics to metastasise
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Angiogenesis at the Molecular Level:
• Step 1: tumours release soluble factors that activate endothelial cells to start
sprouting
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Pro-angiogenic factors include VEGF (A-E), which is the first to be characterised
and most talked about in cancer
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As the cancer progresses, it acquires alternate ways to promote angiogenesis,
such as VEGF-D, growth factors, TGF-beta, which all help to facilitate
angiogenesis
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The tumours become better at inducing and maintaining angiogenesis as the it
progresses
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These factors bind to receptors on endothelial cells to activate them, and in turn,
the endothelial cells upregulate the expression of the receptors
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Platelet derived growth factor (PDGF) is made by endothelial cells and is a key
player in pericyte recruitment
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Hypoxia induces VEGF expression – if a normal cell is in a site in the body where
it’s too far away from the vasculature, the cell has the ability to detect that it is in
a hypoxic environment and induces VEGF expression
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Cells are able to detect hypoxia via the hypoxia inducible factor 1 alpha, which is
expressed by all cells
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Ligand binding leads to the dimerization of the receptors and signalling, with a
single co-receptor attached to the dimers
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Step 3: endothelial cell proliferation and migration
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Step 5: recruitment of pericytes
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RIP-Tag2 mouse is a multi-stage spontaneous mouse model of cancer, where the rat
insulin promoter drives the expression of the SV40 large T-antigen
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Not every cell produces insulin, so it’s only the islets in the pancreas that produce
the viral oncogene, subsequently the mice develops insulinomas
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This viral oncogene blocks retinoblastoma and p53 – taking out tumour suppressor
proteins and now the cells are now primed to undergo further mutations and
transformation to get full blown cancer – insulinomas
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This model is has proved valuable for different experimental questions and is also a
progressive model of the disease
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For example, the islets look quite normal at 5 weeks and use your drug to check if it
can prevent the angiogenic switch occurring
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The angiogenic switch occurs at around 5-7 weeks, where you start to get
transformation of the cells
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RIP-Tag2 mice were given anti-VEGF2R antibodies to block VEGFR2 signalling via
allosteric hindrance
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The antibody slows the tumour growth – there is no regression however
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- Hypoxia inhibits functions of infiltrating immune cells
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- Killing the vessels prevents chemotherapy getting to the tumour – leads to the
generation of a more aggressive cancer
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The normalisation hypothesis is based on the fact that avastin treated tumours are
described as having “normalised” blood vessels:
- Decreased density
- Decreased diameter
- Decreased leakiness
- Decreased interstitial fluid pressure
- Decreased hypoxia
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