Lecture 29 Flashcards
Why must tumours undergo processes of angiogenesis?
Cells need to be close to blood vessels (200 micrometres/10 cell divisions)
In order for tumours to therefore grow to large sizes blood vessels must then be grown or recruited
What are the abnormal blood vessel structures found in tumours?
Reduced basement membranes, pores in endothelial cells and incomplete eptiehlialcell lining, formation of sinusoids
Lack of smooth muscle, pericytes, nerves
Blind endings, direct connections between arteries and veins, tortuous capillaries, uneven distribution
Poor lymphatic drainage within the tumour
What is the abnormal vessel function is derived from reduced basement membranes, pores in endothelial cells etc in tumour blood vessels?
Increased permeabilty, oedema
increased interstitial pressure
What is the abnormal vessel function derived from the lack of smooth muscle, pericytes and nerves in tumour blood vessels?
Reduced control of blood flow
What is the consequence of the blind endings and arteriovenous shunts seen in tumour blood vessels?
Ineffective perfusion, chaotic, intermittent and retrograde blood flow
What is the consequence of the poor lymphatic drainage seen in tumours?
Increased interstitial pressure, drainage of fluid and metastic cells occur in peripheral lymphatics
What the properties of the poorly formed and poorly functional blood vessels in tumours result in?
Hypoxic and acidic regions in tumours which results in a more aggressive cancer as it selects for hypoxic resistant cell this results in the ineffictivenness of radiation therapy due to its oxygen requirement and resistance to anticancer drugs as hypoxc cells will leavethe cell cycle
What factors induce angiogenesis?
Metabolic Stress
Inflammation
Activation of oncogenes or loss of tumour suppressor genes
What is angiogenic sprouting?
When capillaries grow into the tumour from existing capillaries
What are the 3 stages of development of pancreatic islet tumours?
Hyperplastic islets where there is a high S phase fraction due to the induction of IGF2
Angiogenic islets induces the ingrowth of endoothelial cells due to MMP-9
Carcinomas which invade following the deletion of E-cadherin
What is the behavior of endothelial cells in angiogenesis?
When appropriately stimulated, the endothelial cells will degrade a patch of basement membrane, change shape and invade the stroma, this results in the formation of a migratory tip followed by a proliferating stalk and differentiating cells. These migrating cells will eventually form a new capillary
What is the rate determining stage in angiogenic sprouting?
When MMP-9 begins to get secreted, termed the angiogenic switch
What are the observed phases in ductal breast carcinomas?
Hyperplastic ducts
Dysplastic ducts
angiogenic dysplastic ducts
invasive ductal carcinomas
What is co-option of existing blood vessels?
When tumours grow around existing blood vessels the co-opted vasculature then regresses resulting in an avascular tumour with large cell loss, the remaining tumour will initiate angiogenesis
What is intussusception?
Tumours grow into blood vessel lumens of pre-existing blood vessels forcing them to remodel and expand
What is vasculogenesis?
formation of blood vessels requiring angioblasts (precursor cells)
What occurs in incorporation of endothelial cell precursors?
Angioblasts home into stem cells from the bone marrow, they differentiate into endothelial cells or smooth muscle and pericytes
The pathway taken is dependent on the ratio of VEGF/PDGF
How are capillaries formed by cancer cells?
Trans-differentation of cancer cells allows expression of endothelial cell characteristics form capillaries through vasculogenic mimicry
Why is vasculogenic mimicry important when considering cancer?
Cancer capillaries may be lined by both endothelial cells and cancer cells allowing many cancer cells to be shed into the blood to form metastasis
What is the role of VGEF in formation of blood vessels?
VGEF binds to tyrosine kinase receptors on endothelial cells driving endothelial cell survival, proliferation, migration, differentiation and vascular permeability
On its own it will result in immature, leaky, haemorrhagic vessels causing inflammation and oedema
What induces VGEF expression?
Hypoxia inducible factor 1 alpha
in normal oxygen levels this protein is bound to von-hippel lindau protein (VHL) which drives ubquitin conjugation and proteasome degradation
What are the naturally occurring inhibitors of angiogenesis?
Angiostatin (fragment of plasmogen)
Endostatin (fragment of collagen XVIII)
Why can surgical removal of a primary tumor lead to metastases development?
Primary tumors sometimes express inhibitors of angiogenesis, therefore removal of these tumours results in a drop of these inhibitiors allowing metastases to develop
What are the potential cancer treatments derived from controlling angiogenesis?
Monoclonal antibodies against VGEF, these however have the problem of being highly specific and therefore do not work against other angiogenic factors also induced under hypoxic conditions
Inhibition of VEGFR through low molecular weight synthetic inhibitors inhibiting the Tyrosine kinase activity
Low Molecular weight compounds like angioinhibins of fungal origin which inhibit endothelial proliferation
Naturally occuring angiogenic inhiitors works well in mice but not in humans
Protease inhibitors could be used as protease activity is a required factor of angiogensis, however this is ineffective as proteases also generate anti-angiogenic peptides
