Angiogenesis lecture 17 Flashcards
Explain the role of angiogenesis in cancer pathogenesis
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
Used in pathological processes such as cancer
HIF-1 is the Master regulator of oxygen homeostasis and stimulation of angiogenesis.
In high O2 it is degraded:
- Proline hydroxylase hydroxylates residues on HIF-1alpha
- This is recognised by pVHL which catalyses its polyubiquitation. This causes its degradation
In low O2 it is stabilised
- Not sufficient oxygen to drive Proline hydroxylation
- HIF-1alpha is not degraded and can associate with HIF-1beta which induces transcription of genes required for adaptation to hypoxic conditions (such as VEGF)
Steps of angiogenesis
1) VEGF regulated VE-cadherin and loosens endothelial junctions
2) Increased permeability allows the deposition of plasma proteins to make a provisional matrix
3) Endothelial cells secrete proteases to remodel existing interstitial matrix
4) Selection of tip cell to guide the newly forming sprout- filopodia sense the extracellular environment and secrete VEGF .
5) Pericyte detachment mediated by Angiopoeitin
6) Tip cells navigate in response to guidance signals and adhere to the extracellular matrix (mediated by integrins) to migrate
7) Notch signalling between the tip (delta-like 4/DL4) and stalk cells (notch) maintains their different specification. Cells express DL4 which signals by notch to neighbouring cells and downregulates tip cels forming.
8) Stalk cells behind the top proliferate and extend the sprout- VEGFR-2 is down regulated
9) Formation of the lumen in the newly developing sprout
10) Stalk attracts pericytes to stabilise the newly formed vessels
11) Sprouts from adjacent vessels grow towards each other
12) Angiopoeitin 1 signalling between endothelial cells and pericytes maintain quiescence of the vessel
13) Formation of tight junctions, basement membrane deposition, pericytes maturation
What is the importance of the von hippel lindau protein (VHL)?
Forms part of the recognition component of the E3 ubiquitin kinase for HIF-1a
HIF is modified by proline 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
Describe VEGF in cancer
- VEGF-A is the most potent
- Drives angiogenesis by activation of VEGFR-2 (TK)
- High expression of VEGF correlates with poor prognosis especially in breast cancer
Released from the cancer cells, the extracellular matrix and inflammatory cells (macrophages are associated with increased vessel density)
What is the angiogenic switch?
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)
How can you inhibit VEGF signalling therapeutically and inhibit angiogenesis?
Monoclonal antibody to VEGF- bevacizumab, avastin
Soluble receptor- aflibercept
Small molecule inhibitors of VEGFR- sunitinib, sorafenib
Antibody blocking binding of VEGF too the receptor- IMC 1C11
Inhibit angiongeneis:
INhibit production of angiogenic factors, neutralising antibody, soluble repctor, blocking antibody
What is the clinical significance of bevacizumab?
Little efficacy alone against tumours- only works in conjunction with cytotoxic drugs
Thought that by reducing VEGF signalling it normalises the vasculature in the tumour for more effective delivery of treatment to the tumour
What is the clinical significance of pericytes?
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
What are the potential mechanisms of resistance to VEGF mediated therapy?
Production of angiogenic factors- FGF, chemokines, PIGF, hypoxia tolerance, more invasiveness
Vessels become lined by tumour cells CAF activation and macrophage recruitment
High levels of pericytes coverage
How is tumour vasculature different from normal and what are the clinical implications?
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
