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eMCD - Can > Cancer 8: Angiogenesis > Flashcards

Cancer 8: Angiogenesis Flashcards

1
Q

3 main Physiological angiogenesis:

A

Physiological angiogenesis:

  • Embryonic development
  • Wound healing,
  • Menstrual cycle
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2
Q

What acts as a trigger for angiogenesis?

a) what are the factors involved?
b) how do they work under oxygen / no oxygen conditions

A

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
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3
Q

what areVascular Endothelial Growth Factor (VEGF) ?

what is the main receptor involved in VEGF dep angiogenesis?

A

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

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4
Q

What is the function of Tip cells in angiogenesis?

A

when VEGF released–> specialised endothelial tip cells lead the outgrowth of blood-vessel sprouts towards gradients of VEGF

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5
Q

What determines which endothelial cell becomes the tip cell?

A

Notch signalling

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6
Q

describe the Canonical Notch signalling pathway

???

A
  • controls cell behavior

- ligand + receptors binds –> receptor intracellular tail of Notch is cleaved –> translocated into nucleus –>

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7
Q

How is Selection of Tip cells: via VEGF/Notch signalling done?

A
  1. In stable blood vessels, Dll4 + Notch signalling is quiescent because both = signalling on both cells
  2. VEGF activation increases expression of Dll4
  3. Cell with most Dll4 expression (becomes tip) –> Dll4 drives Notch signalling, which inhibits VEGFR2 (receptor) expression in adjacent cell
  4. Dll4-expressing tip cells acquire a motile, invasive, sprouting phenotype
  5. Adjacent cells (Stalk cells) form base of emerging sprout + proliferate to support sprout elongation.
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8
Q

Describe the process of Sprout outgrowth and guidance

A

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

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9
Q

VE-Cadherins = expressed at ______

what do they do?

A

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

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10
Q

Loss of cadherin control can contrbute to______ cancers

A

Loss of cadherin control can contrbute to epithelial cancers

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11
Q

How do Mural cells help stabilise neovessels?

A
  • Pericytes normally wrap around capillaries

- They produce stabilizing factor Angiopoietin-1

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12
Q

Describe Signalling pathways that control stability: the Angiopoietin-Tie2 ligand-receptor system

A
  • 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

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13
Q

When might Plasma [Ang-2] raised in disease?

i.e Dysregulation of Ang 2 is related to what diseases?

A

Plasma [Ang-2] raised in disease:
ANG 2 = can be dysregulated in diseases e.g

  • Congestive heart failure,
  • Sepsis
  • Chronic Kidney Disease
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14
Q

Tumors < 1 mm3 survive from oxygen + nutrients by:

A

diffusion from host vasculature.

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15
Q

Larger tumors require new vessel network to grow - how is this achieved?

A

-Larger tumors –> secrete angiogenic factors –> stimulate migration, proliferation, + neovessel formation by endothelial cells in adjacent existing host vessels.

–>facilitating progressive growth of tumour

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16
Q

What is the angiogenic switch?

A

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

17
Q

What are some characteristics of tumour blood vessels?

A
  • 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!)
18
Q

What is Anti-VEGF Humanised MAb (AVASTIN) used for?

A

Used (w/ IV 5-fluorouracil) for 1st line treatment of metastatic colorectal carcinoma

other uses:

  • cervical cancer
  • Glioblastoma
19
Q

What are some side effects of Avastin therapy for cancer?

A
  • 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
20
Q

What are the 2 Modes of Resistance to anti-angiogenic (anti-VEGF) cancer therapy? :

A

they may be resistant / less effective because:

  1. Evasive resistance = adaptation to circumvent specific angiogenic blockade
    - -> other angiogenic pathways can take over
  2. 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
21
Q

what are the 2 ways to feed tumour?

A
  1. Angiogenesis:
    - tumour secretes factors –> stimulate vessel growth –> vessel grows into tumour
  2. Tumor cell vasculogenic/vascular mimicry (VM)
    - plasticity of aggressive cancer cells forming de novo vascular networks = is associated with malignant phenotype and poor prognosis.
22
Q

What other uses might

a) Anti-angiogenic therapy have ?
b) Pro-angiogenic therapy have ?

A

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)

23
Q

Describe the importance of Therapeutic Angiogenesis for Coronary Artery Disease + Peripheral Artery Disease:

A
  • esp in isachaemic damage / disease
  • -> neo-vascularisation is promoted
  • -> e.g VEGF injected
  • -> to allow revascularisation of occluded parts of the myocardium
24
Q

What are the 3 ways to make a blood vessel?

A
  • progenitor from one marrow –> initiates blood vessel formation (vasculogenesis)
  • sprouting angiogenesis
  • arteriogenesis
25
Q

Give a brief overview of sprouting angiogenesis

A

trigger = hypoxia
–> GF activates endothelial cells –> causes epithelial cells to undergo change in confrormation –> causes sprouting –> towards GF

tip cells fuse with another sprout –> restailises new capillaries

26
Q

What is the importance of “tumour on a chip”

A
  • tumour on a chip

- -> allows you to see effective ness of drugs/various mediums on their effect on tumour cells

eMCD - Can (15 decks)

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