Angiogenesis

Question 1

Why is Angiogenesis important for tumours?

Answer 1

• As tumours grow they require additional delivery of oxygen and nutrients. The lack of oxygen results in hypoxia
• triggers production and secretion of Vascular Endothelial Growth Factor (VEGF) which acts on nearby blood vessels to cause sprouting of endothelial cells in the direction of the tumour. Delivering oxygen to deprived areas
• Without blood supply tumour mass is restricted to 1-2mm diameter

Question 2

Mechanism of Angiogenesis

Answer 2

• Involves proliferation and migration of resident endothelial cells
• Angiogenic signals released by tumour
• Stromal cells also contribute
• Less organised capillary network, less pericytes in tumours, less control of cells

Question 3

Vascular Endothelial Growth Factor (VEGF)

Answer 3

• 5 types (A-E), A strongly linked to cancer and generally found in dimer
• VEGF is produced in response to
  hypoxia via activation of the
  transcription factor HIF1α

Question 4

VEGF Receptors

Answer 4

VEGFR-1 = Function not well known

VEGFR-2 = Most responsible for angiogenesis, can bind to VEGF-A and
VEGF-C as its main ligands

VEGFR-3 = Involved in lymphangiogenesis

Receptors dimerise upon ligand binding and have kinase activity in the
intracellular domain = type of tyrosine kinase receptor

Question 5

VEGF Signalling

Answer 5

• Occurs in the endothelial cells

Question 6

Endothelial Cell Response

Answer 6

Question 7

Endogenous Angiogenesis Inhibitors

Answer 7

• 30 known inhibitors
• Many derived from ECM components degraded by invading cancer cells such as collagen
• Target proliferating and
  migrating endothelial cells
• Breakdown of Type IV collagen by matrix metalloproteases (MMPs) secreted by invading cancer cells generates inhibitors

Question 8

Endostatin

Answer 8

Inhibitor developed as a drug
- 20 kDa C-terminal fragment derived from type XVIII collagen
- Clinical trials suggested benefits but results led to development of other drugs

Question 9

Targets for anti-angiogenesis therapy

Answer 9

• VEGF
• VEGF receptors
• FGF receptor signalling
• Semaphorins

Question 10

Failure of anti-angiogenesis therapies

Answer 10

• Many aggressive tumour are poorly vascularised
• In these cases hypoxia drives tumours to grow faster and overgrow existing blood vessels in tissues
• May explain failures in therapies as it will drive tumour growth in effort to seek oxygen

Question 11

Vascular Co-option

Answer 11

• Tumour cells co-opt existing blood vessels in tissue rather than cause new ones to grow
• Displace normal cells
• Tumour grows around rather than over existing blood vessels, keeping them open and maximising blood flow to growing tumour
• Non-angiogenic vascular co-option can also be seen during growth of metastasis

Question 12

Paper

Answer 13

hTERT = Catalyses extension of telomeres
Cancer linked with changes in expression
ALT mechanism - homologous recombination

Question 14

Why use GM847 cells?

Answer 14

Immortal cells and don’t express telomerase (ALT Mechanism)

Question 15

3 things required to transform cells into a tumourigenic state

Answer 15

• Knock SV40 (tumour suppressor) out
• Over express Ras oncogene
• hTERT to lengthen telomeres