Chapter 11 Flashcards
Which VEGF and VEGFR are most responsible for the angiogenic response in normal angiogenesis?
VEGF-A on VEGFR2
What is the result of increased VEGF?
1- Dilatation and formation of a mother vessel
2- Detachment of the mural cells
3- Upregulattion of Angiopoientin 2 which inactivate Tie-2 = reduced pericyte and endothelial cell contact resulting in liberated endothelial cells
- formation of VEGF sensing endothelial sprouts which contain VEGFR2 receptors
- The sporout cell will follow VEGF gradient
Which VEGFs are mainly responsible for lymphangiogenesis?
VEGF C/D
By which 3 mechanisms may angiogenesis occur? and which one is most common cancer?
Intussusception, vascular splitting, sprouting, the latter is the main form in cancer
How is angiogenesis initiated in a tumour?
A precapillary vessel is exposed to a gradient of proangiogenic substances - such as VEGF expression induced by hypoxia.
Which cellular signalling pathway is important in angiogenesis?
The notch pathway
How are proteinases involved in normal angiogenesis?
MMPs are important for liberating endothelial cells by dissolving the capillary basement membrane and release agnigeic factors from the ECM store.
What is vascular cooption?
When cancer cells exploit pre-existing vasculature by grown around and eveloping the vessel. Will however result after time in blood vessel regression and thrombosis
Which effect does VEGF-A have on endothelial cell?
Promote angiogenesis, is a potent mitogen, stimulate mobility and survival and chemoattractant for EC progenitor cells
What is the main effect of PDGF in angiogenesis?
Vascular maturation
What is the main function of angiopoietins and their binding to TIE receptors?
They mediate EC survival, vascular permeability and recruitment of mural cells
What happens when angiopoietin expression is high, but VEGF is low?
It does not promote vascular sprouting without VEGF and will result in promotion of vascular regression.
Name the most important factors stimulating angiogenesis?
VEGF, PlGF, FGF1/2, HGF, IL-8 - these factors works directly on Ecstatics
TGF alpha, beta, and other cytokines may also stimulate angiogenesis indirectly by promote release and production of the factors above.
Name the most important inhibitors of angiogenesis?
Thrombospondins 1 and 2, fragments of coagulation related chemockines, and hormones, cytokines (INF)
Which cytokines is known to inhibit tumor angiogenesis?
Interferon alpha, beta and gamma
What is the target for the majority of antiangiognic drugs used today?
VEGF or VEGFR
Which mechanisms will trigger tumour neovascularisation?
The preangiogenic phase is defined by hypoxia and lack of macromolecules, and the cells ability to survive such conditions. Beyond perivascular diffusion the cancer cells will either undergo growth arrest or enter a state of dormancy. Exposure to these conditions can drive the onset of angiogenesis.
Aggiogenesis is often attributed to the agnigeic switch- how does cancer cells “turn on” angiogenesis?
- directly by production of angiogenic factors
2. by causing hypoxic shift in the microenvironment, recruit stromal cells and induce inflammation
How does hypoxia trigger angiogenesis?
Hypoxia induce HIF-1/2 expression, and his have several angiogenesis related targets in its pathway including VEGF, SDF1, ANG2, PlGF, PFGF, stew cell factor and VEGEFR1. It also lead to down regulation of angiogenesis inhibitors such as thrombospondin 1
Cancer cells can express proangiogenic properties also without hypoxia, which ones?
VEGF, Ras, Src, Myc, EGFR, HER2, i addition to loss of function affecting p53, PTEN, p16 and VHL
What is the result of oncogenic mutations on angiogenesis?
1) Upregulation of vascular stimulators such as VEGF, FGF, IL-6, IL-8 and ANG-1 and downregulation of inhibitory factors such as TSP, endostatin and tumstatin.
How is tumour angiogenesis affected by inflammation?
The inflammation can be initiated by infection, immunactivation, oncogenic mutations or the microenvironment, result in recruitment of inflammatory cells such as macrophages and myeloid cells- these produce proteolytic enzymes, pro-angiogenic growth factors, cytokines and chemokine eg. VEGF-A and IL-8
Which main factors can initiate tumour angiogenesis?
Hypoxia Lack of nutrients and macromolecules Ongenic mutations Inflammation Tumour stromal cells
which other factors impact tumour angiogenesis?
- Genetic polymorphism of the host
- Age of the host
Others include the tumour microcirculation itself, lymphatic drainage and CSC
Which antiangiogenic drugs target VEGF?
Bevacizymab- colorectal cancer
Which antiangiogenic drugs target VEGFR?
Sunitinib-
Sorafenib-
What is the MAO for thalidomide?
it inhibits angiogenesis through inflammatory pathways- a small molecule. Uses in MM
Which oncogenes stimulate tumour angiogenesis?
HER-2 (ERBB2), EFGR, RAS
Name 4 main strategies to target tumour angiogenesis and an example of drug developed for inhibition?
- Targeting oncopathways such as EGFR, HER-2, Myc, sir - drug example; trastuzumab
Which factors are involved in the angiogenic switch?
Pre-agniogenic: overweight antiangiogenic factors- TSP-1, PEDF, PED
Angiogenic: VEGF expression outweigh the antiangiogenic factors
Name 2 non-angiogenic mechanisms tumour cells use for to access vasculature?
- Vascular cooption
2. Vasulogenic mimicry
How can cancer cells influence or initiate angiogenesis?
- Produce proangiogenic factors
- Indirectly through the shift in tissue microenvironent resulting in recruitment of proangigoenic stromal cells
- Induce inflammatory response
Name 5 stimulatory factors involved in tumour angiogenesis?
FGF IL-8 IL-6 TNF-alpha MMP9
Explain the angiogenic switch?
When tumour induced signalling result in net stimulatory activity overriding the inhibitory mechanisms initiation angiogenesis.
How can tumours induce angiogenesis?
- Directly through mutations in oncogenes and tumour suppressor genes, alteration in the mediations of the angiogenic switch
- Indirectly
- hypoxia
- inflammation
- recruitment of stromal cells
- PLT / coagulation factors
How does hypoxia influence angiogenesis?
- Induce HIF- transcription factor for VEGF, CXCL12, ANG2, PDGF and inhibitory for TSP-1
- Induce localised VEGF production
- Stimulate arteriogenesis via NO resulting in feeding vessel development
How does inflammation stimulation angiogenesis?
- Recruit tumour macrophages which produce VEGF-A and IL-8
.How does tumour associated stromal cells influence angiogenesis?
Produce VEGF A
How does platelet and coagulation stimulate angiogenesis?
Thrombin, thomboplastin and platelet increase VEGF and IL-8
