Cancer 8: Angiogenesis Flashcards
3 main Physiological angiogenesis:
Physiological angiogenesis:
- Embryonic development
- Wound healing,
- Menstrual cycle
What acts as a trigger for angiogenesis?
a) what are the factors involved?
b) how do they work under oxygen / no oxygen conditions
trigger = hypoxia
protein
- HIF: (hypoxia-inducible transcription factor)–> controls regulation of gene expression by oxygen
- pVHL: (Von Hippel–Lindau) Tumour Suppressor Gene –> controls HIF levels
With sufficient oxygen:
- pVHL binds HIF –> induces ubiquitination in HIF –> HIF degraded
- When no oxygen:
- pVHL doesn’t bind HIF –>HIF not degraded –> more enters nucleus + binds HIF-beta –> drives transcription of genes promoting angiogenesis e.g. VEGF
what areVascular Endothelial Growth Factor (VEGF) ?
what is the main receptor involved in VEGF dep angiogenesis?
VEGF = activator of angiogenesis
- regulator of angiogenesis
- 5 family A/B/C/D + PIGF
binds to VEGF 2 receptor = main receptor involved in VEGF dependent angiogenesis
What is the function of Tip cells in angiogenesis?
when VEGF released–> specialised endothelial tip cells lead the outgrowth of blood-vessel sprouts towards gradients of VEGF
What determines which endothelial cell becomes the tip cell?
Notch signalling
describe the Canonical Notch signalling pathway
???
- controls cell behavior
- ligand + receptors binds –> receptor intracellular tail of Notch is cleaved –> translocated into nucleus –>
How is Selection of Tip cells: via VEGF/Notch signalling done?
- In stable blood vessels, Dll4 + Notch signalling is quiescent because both = signalling on both cells
- VEGF activation increases expression of Dll4
- Cell with most Dll4 expression (becomes tip) –> Dll4 drives Notch signalling, which inhibits VEGFR2 (receptor) expression in adjacent cell
- Dll4-expressing tip cells acquire a motile, invasive, sprouting phenotype
- Adjacent cells (Stalk cells) form base of emerging sprout + proliferate to support sprout elongation.
Describe the process of Sprout outgrowth and guidance
progress requires proliferation + stalk elongation
ECM –> important for binding of GF
- pericyte recruitment –> binds to outside of new sprout –> stabilizes signal
–> establishes contact btw epithelial cells
VE-Cadherins = expressed at ______
what do they do?
VE-Cadherins = expressed at junctions
Junction =where cells get signals from each other
they:
- Mediates adhesion between endothelial cells
- Controls contact inhibition of cell growth
- Promotes survival of EC
–> allows stabilization of junctions
Loss of cadherin control can contrbute to______ cancers
Loss of cadherin control can contrbute to epithelial cancers
How do Mural cells help stabilise neovessels?
- Pericytes normally wrap around capillaries
- They produce stabilizing factor Angiopoietin-1
Describe Signalling pathways that control stability: the Angiopoietin-Tie2 ligand-receptor system
- Ang-1/2 are antagonistic (to each other) ligands of Tie2 receptor (endothelial)
- 2 factors Ang 1 (good) vs Ang 2(bad)
- compete for tie2 receptor
- Ang-1 binding to Tie2 –> vessel stability + anti-inflammatory gene expression,
Ang-2 (growth, stored in endothelial cells) antagonises Ang-1 signalling –> promotes vascular instability + VEGF-dependent angiogenesis
When might Plasma [Ang-2] raised in disease?
i.e Dysregulation of Ang 2 is related to what diseases?
Plasma [Ang-2] raised in disease:
ANG 2 = can be dysregulated in diseases e.g
- Congestive heart failure,
- Sepsis
- Chronic Kidney Disease
Tumors < 1 mm3 survive from oxygen + nutrients by:
diffusion from host vasculature.
Larger tumors require new vessel network to grow - how is this achieved?
-Larger tumors –> secrete angiogenic factors –> stimulate migration, proliferation, + neovessel formation by endothelial cells in adjacent existing host vessels.
–>facilitating progressive growth of tumour
What is the angiogenic switch?
angiogenic switch = point where tumour becomes dependent on angiogenesis for growth
note: an occur at different stages in tumour-progression pathway, depending on tumour’s nature + microenvironment
What are some characteristics of tumour blood vessels?
- irregularly shaped, dilated, tortuous
- not organized into definitive venules, arterioles and capillaries –> because they are triggered by angiogenic factors (not through balance)
- leaky and haemorrhagic, partly due to excessive VEGF
- perivascular cells are often loosely associated
- some tumours may recruit endothelial progenitor cells from the bone marrow (controversial!)
What is Anti-VEGF Humanised MAb (AVASTIN) used for?
Used (w/ IV 5-fluorouracil) for 1st line treatment of metastatic colorectal carcinoma
other uses:
- cervical cancer
- Glioblastoma
What are some side effects of Avastin therapy for cancer?
- GI perforation
- Hypertension
- Proteinuria
- Venous thrombosis
- Haemorrage
- Wound healing complications
studies have shown:
- no overall survival advantage over chemo alone
- no significant advantage in terms of quality-of-life or survival
What are the 2 Modes of Resistance to anti-angiogenic (anti-VEGF) cancer therapy? :
they may be resistant / less effective because:
- Evasive resistance = adaptation to circumvent specific angiogenic blockade
- -> other angiogenic pathways can take over - Intrinsic or pre-existing indifference, if tumour more dependent on different GF
note: also preventing blood flow to cancer –> compromises effects of chemotherapy –> less blood flow to cancer troll carry out effects of chemotherapy
what are the 2 ways to feed tumour?
- Angiogenesis:
- tumour secretes factors –> stimulate vessel growth –> vessel grows into tumour - Tumor cell vasculogenic/vascular mimicry (VM)
- plasticity of aggressive cancer cells forming de novo vascular networks = is associated with malignant phenotype and poor prognosis.
What other uses might
a) Anti-angiogenic therapy have ?
b) Pro-angiogenic therapy have ?
Anti-angiogenic:
a) treat abnormal retina vascularization (diabetic retinopathy, wet AMD) - Anti VEGF therapy
- Age-related macular degeneration (AMD) = abnormal growth of choroidal blood vessels –> leaky vessels cause oedema, also visual impairment
Pro-angiogenic
b) for ischemic diseases (MI, peripheral ischemic disease)
Describe the importance of Therapeutic Angiogenesis for Coronary Artery Disease + Peripheral Artery Disease:
- esp in isachaemic damage / disease
- -> neo-vascularisation is promoted
- -> e.g VEGF injected
- -> to allow revascularisation of occluded parts of the myocardium
What are the 3 ways to make a blood vessel?
- progenitor from one marrow –> initiates blood vessel formation (vasculogenesis)
- sprouting angiogenesis
- arteriogenesis
