Angiogenesis

Question 1

Explain the role of angiogenesis in cancer pathogenesis

Answer 1

Critical for tumour growth
Vessel formation- angiogenesis, vasculogenesis, intersusception, vessel co-option (common in lung cancer when the tumour fills the alveoli using the existing capillary network, vascular mimicry, endothelial differentiation
Angiogenesis is stimulates by hypoxia- in oxygen deprived situation HIF-1a is not degraded by polyubiquitination and HIF-1a drives the transcription of VEGF

Question 2

What is the importance of the von hippel lindau protein?

Answer 2

Forms part of the recognition component of the E3 ubiquitin kinase for HIF-1a
HIF is modified by proliner hydroxylase so pVHL can recognise it and provide specificity for the E3 ubiquitin ligase
Von-Hippel Lindau disease- autosomal dominant cancer syndrome predisposes patients to clear-cell carcinoma of the kidney, phaeochromocytoma, hemangioblastomas of the CNS and retina

Question 3

Describe VEGF in cancer

Answer 3

High expression of VEGF correlates with poor prognosis
Released from the cancer cells, the extracellular matrix and inflammatory cells (macrophages are associated with increased vessel density)

Question 4

What is the angiogenic switch?

Answer 4

There is a number of pro and anti angiogenic factors that determine whether angiogenesis begins
Angioigeneis occurs when the effect of the angiogenic activators (eg. VEGF-A,B,C, FGF1,2) is greater than those of the inhibitors (eg. Thromnospondin-1,2, interferon, angiostatin, endostatin)

Question 5

How can you inhibit VEGF signalling therapeutically?

Answer 5

Monoclonal antibody to VEGF- bevacizumab
Soluble receptor- aflibercept
Small molecule inhibitors of VEGFR- sunitinib, sorafenib
Antibody blocking binding of VEGF too the receptor- IMC 1C11

Question 6

What is the clinical significance of bevacizumab?

Answer 6

Little efficacy alone against tumours- only works in conjunction with cytotoxic drugs
Thought that by reducing VEGF signalling it normalises the vasculature in gthe tumour for more effective delivery of treatment to the tumour

Question 7

What is the clinical significance of pericytes?

Answer 7

Provide survival functions and are partially resistant to VEGFR inhibition
Using PDGF receptor inhibitors you can target pericytes and the endothelial cells are very sensitive to VEGFR inhibition and chemotherapy
Sorafenib, sunitinib and pazopanib inhibit VEGFR and PDGFR and are used as a monotherapy

Question 8

What are the potential mechanisms of resistance to VEGF mediated therapy?

Answer 8

Production of angiogenic factors- FGF, chemokines, PIGF, hypoxia tolerance, more invasiveness
Vessels become lined by tumour cells
CAF activation and macrophage recruitment
High kevels of pericytes coverage

Question 9

How is tumour vasculature different from normal and shat are the clinical implications?

Answer 9

Tortuous
Leaky
Variable flow
High interstitial pressure- poor lymphatic drainage
Lacking normal hierarchical structure
Acidic and hypoxia conditions lead to differential gene expression- find tumour endothelial markers
Nanoparticles will accumulate preferentially in the tumours to the high permeation and retention