Lecture 29

Question 1

Why must tumours undergo processes of angiogenesis?

Answer 1

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

Question 2

What are the abnormal blood vessel structures found in tumours?

Answer 2

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

Question 3

What is the abnormal vessel function is derived from reduced basement membranes, pores in endothelial cells etc in tumour blood vessels?

Answer 3

Increased permeabilty, oedema

increased interstitial pressure

Question 4

What is the abnormal vessel function derived from the lack of smooth muscle, pericytes and nerves in tumour blood vessels?

Answer 4

Reduced control of blood flow

Question 5

What is the consequence of the blind endings and arteriovenous shunts seen in tumour blood vessels?

Answer 5

Ineffective perfusion, chaotic, intermittent and retrograde blood flow

Question 6

What is the consequence of the poor lymphatic drainage seen in tumours?

Answer 6

Increased interstitial pressure, drainage of fluid and metastic cells occur in peripheral lymphatics

Question 7

What the properties of the poorly formed and poorly functional blood vessels in tumours result in?

Answer 7

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

Question 8

What factors induce angiogenesis?

Answer 8

Metabolic Stress
Inflammation
Activation of oncogenes or loss of tumour suppressor genes

Question 9

What is angiogenic sprouting?

Answer 9

When capillaries grow into the tumour from existing capillaries

Question 10

What are the 3 stages of development of pancreatic islet tumours?

Answer 10

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

Question 11

What is the behavior of endothelial cells in angiogenesis?

Answer 11

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

Question 12

What is the rate determining stage in angiogenic sprouting?

Answer 12

When MMP-9 begins to get secreted, termed the angiogenic switch

Question 13

What are the observed phases in ductal breast carcinomas?

Answer 13

Hyperplastic ducts
Dysplastic ducts
angiogenic dysplastic ducts
invasive ductal carcinomas

Question 14

What is co-option of existing blood vessels?

Answer 14

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

Question 15

What is intussusception?

Answer 15

Tumours grow into blood vessel lumens of pre-existing blood vessels forcing them to remodel and expand

Question 16

What is vasculogenesis?

Answer 16

formation of blood vessels requiring angioblasts (precursor cells)

Question 17

What occurs in incorporation of endothelial cell precursors?

Answer 17

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

Question 18

How are capillaries formed by cancer cells?

Answer 18

Trans-differentation of cancer cells allows expression of endothelial cell characteristics form capillaries through vasculogenic mimicry

Question 19

Why is vasculogenic mimicry important when considering cancer?

Answer 19

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

Question 20

What is the role of VGEF in formation of blood vessels?

Answer 20

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

Question 21

What induces VGEF expression?

Answer 21

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

Question 22

What are the naturally occurring inhibitors of angiogenesis?

Answer 22

Angiostatin (fragment of plasmogen)

Endostatin (fragment of collagen XVIII)

Question 23

Why can surgical removal of a primary tumor lead to metastases development?

Answer 23

Primary tumors sometimes express inhibitors of angiogenesis, therefore removal of these tumours results in a drop of these inhibitiors allowing metastases to develop

Question 24

What are the potential cancer treatments derived from controlling angiogenesis?

Answer 24

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