Angiogenesis and cancer treatment Flashcards

1
Q

What are the functions of angiogenesis?

A
  • blood vessels supply oxygen, nutrients, remove waste and allow immune surveillance
  • angiogenesis is essential for organ growth in the embryo and repair of wounded tissue in the adult
  • abnormal angiogenesis leads to disease:
  • insufficient vessel growth (stroke, MI)
  • excessive vessel growth (cancer, inflammatory disorders)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What are the 3 types of angiogenesis?

A
  1. developmental/ vasculogenesis = organ growth
  2. normal angiogenesis = wound repair placenta during pregnancy, cycling ovary
  3. pathological angiogenesis = tumour angiogenesis, ocular and inflammatory disorders
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What are some pro and anti-angiogenic factors?

A

pro-angiogenic
- VEGF, PDGF, TGF-alpha, MMPs
anti-angiogenic
- thrombospondin 1 and 2, TIMPs, angiostatin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What is the angiogenic switch?

A

an imbalance between stimulus and inhibitors

- balance is shifted so stimulus is excessive resulting in malignant, ocular and inflammatory disorders

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is tumour hypoxia?

A
  • hypoxia is a strong stimulus for tumour angiogenesis
  • hypoxia - low oxygen tension < 1% O2
  • increases with increasing distance from capillaries
  • activates genes (VEGF, GLUT-1) involved in angiogenesis, tumour cell migration and metastasis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What are the characteristics of abnormal vessels in tumours?

A
  • leaky
  • heterogenous
  • tortuous serpentine
  • irregular branching
  • abnormal shunts
  • poor drug delivery - less sensitive to chemoradiation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Describe transcriptional regulation of tumour angiogenesis

A
  • HIF - hypoxia inducible factor
  • transcription factor regulates hypoxia induced gene transcription
  • heterodimer, HIF-1a and HIF-1beta subunits =
  • HIF-2a
  • HIF-1/2a levels are tightly regulated by O2 and are degraded in normoxia, but stabilised in hypoxia
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Describe VEGF siganlling

A
  • VEGF is the main component binds VEGFR-1 and VEGFR-2 with VEGFR-2 having the predominant role
  • neuropilins (NRP1, NRP2) are VEGF co-receptors but can also signal independently
  • VEGF-B has restricted angiogenic activity eg in heart
  • VEGF-C and VEGF-D involved in vasculogenesis and lymphangiogenesis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

VEGF signalling pathways

A
  • VEGF regulates several endothelial cell functions -eg, proliferation, differentiation, permeability, vascular tone, and production of vasoactive molecules
  • upon ligand binding, the receptor tyrosine are phosphorylated, allowing the receptor to associate with and activate a range of signalling molecules:
  • PIK3 = leading to PKB activation and cell survival
  • PLC- g leading to cell proliferation, vasopermeability and angiogenesis
  • MAPK cascade via Raf stimulation leading to gene expression and cell proliferation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What are the types of blood vessel recruitment?

A

a) sprouting angiogenesis - most widely described and accepted
b) vasculogenesis - vessel formation by endothelial progenitor cells
c) intussusception - splitting of pre-exisiting vessels into two daughter vessels
d) vessel co-option - cancer cells grow around and co-opt existing vasculature
e) vascular mimicry - cancer cells become incorporated into the vessel wall
f) tumour SC to EC differentiation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

molecular basis of sprouting angiogenesis I

A
  • angiogenic stimulus
  • quiescent vessel dilates
  • tip cell selected
  • pericyte detachment (ANG-2)
  • loosening of EC junctions (VE-cadherins)
  • increased vascular permeability
  • degradation of basement membrane
  • cell migration
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

molecular basis of sprouting angiogenesis II

A
  • tip cell navigates in response to guidance signals
  • adheres to ECM via integrins
  • stalk cells behind tip proliferate, elongate and form a lumen
  • sprouts fuse to establish perfused neovessel
  • stabilisation of vessel of by pericyte recruitment
  • myeloid cells (tumour cells associated macrophages secrete angiogenic factors)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

molecular basis of sprouting angiogenesis III

A
  • fusion of branches and re-establishment of quiescence, lumen formation and vessel perfusion
  • cell junctions tighten
  • deposition of basement membrane
  • maturation of pericytes
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Describe metastatic renal cell carcinoma therapy

A
  • prior to 2005 IL-2 was the only FDA approved drug for advanced RCC
  • since 2005, 8 new targeted therapies
  • 2 classes of inhibitors:
  • inhibitor of angiogenesis (anti-VEGF)
  • mTOR pathway
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What are the targeted anti-angiogenic therapies?

A
  • Anti-VEGF = avastin
  • receptor tyrosine kinase inhibitors = sunitinib, sorafenib
  • mTOR - everolimus, temsirolimus
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What are the limitations of anti-angiogenic therapy?

A
  • not a cure
  • anti-angiogenic agents extend life in some but not all tumour types
  • resistance to anti-VEGF therapies develop
  • vessel regression does not kill off the tumour but can cause regions of excessive hypoxia thereby stimulating upregulation of tumourigenic genes
17
Q

What are some future directions for anti-angiogenic therapy?

A
  • combinatorial regimens in clinical trials - combining different classes of targeted anti-angiogenic drugs
  • novel targets - angiopoietins, non-VEGF pathways
  • HIF-2alpha inhibitors (PT2385) alone or in combination with other targeted agents hold future promise as anti-cancer therapeutics
18
Q

What is the recent research with HIF-2 inhibitors?

A
  • phase I clinical trials with PT2385
  • no dose limiting toxicity
  • 2% complete response, 12% partial response, and 52% stable disease in heavily pretreated ccRCC patients
  • potential acquired resistance mutations