Tumour angiogenesis Flashcards
What is angiogenesis? What is it for normally?
New endothelial cells from pre-existing ones that will form new vessels. Development and growth, wound healing, reproductive system and muscle growth after exercise.
What are capillaries made of and what is their functions?
Pericytes, basement membrane, and single endothelial layer
What is the consequences of angiogenesis in disease?
Excessive: Tumour metastasis and growth Arthiritis Vascular malformation Insufficient: Coronary artery disease myocardial infraction
What activates angiogenic switch?
Hypoxia, nutrient depletion and oncogenes. Through growth factors mostly and cytokines that bind to receptors on cell surface and mediate processes such as prolferation, migration, differnetiation
List some pro and anti angiogenic factors
Pro: FGF, HGH, VEGF, ang2, ang1, EGF, IL8, MMP
Anti: Thrombostin, endostatin, platelet factor 4, fibronectin
List the steps in sprouting angiognesis
- Production and release of angiogenic factors
- Activation by binding to endothelial cells:
There will be degradation of ECM and remodelling
Loosening of cell cell adhesion
Tip cell selection Proliferation and migration of tip cells
Proliferation of stalk cells
Form a vascular lumen and capillaries
Stabilize junction
Recruit pericyte and vessel maturation
What is the functions of VEGF?
- Permeabilize the vessels
- Migrate, proliferate, survival of endothelila cells
- Trigger matrix degrading protease
- Promoter of endothelial cells to a 3D vessel
What are the members of VEGF family? and which ones are involved in cancer?
VEGFA, VEGFB, C, D, placental growth factor. A,B associated with cancer
What is the difference/similarities in gene structure between these VEGF’S?
VEGF A has 8 exons and the rest have 7, VEGF A has heparin domain that is positively charged. They all have different proteins with different functions, they are all on different chromosomes. But have homologous VEGF domain
How is VEGF family so diverse with so many isoforms?
They undergo alternative splicing, proteolysis to produce active forms
Explain how hypoxia regulates VEGF expression
Normoxia HIF is destabilized via hydroxylation and ubiquitylated and degraded. But in hypoxia there will be stabilizationn because VHL will be degraded and it’ll translocate to the nucleus and dimerize with HIFB and transcribe VEGF genes and angiogenesis will ensue
VEGF expression by tumour cells will bind to receptors on endothelial cells what are those receptors?
Heparan sulfate proteoglycan
soluble VEGFR
Tyrosine kinase receptors
Neuropilin co-receptor
VEGF TKR how does it work when it binds to VEGF?
Receptor dimerize, receptor activated and phosphorylated in the intracellular domain and then activates downstream targets
How does soluble VEGFR work?
It is the ectodomain of VEGFR, it traps the VEGF and prevents it from activating the intracellular domain in transmembrane receptors
How does neuropilin co-receptor work?
It binds to VEGF A forms a VEGF ddependent complex and this will change the pathways that are activates, it enhances the signalling by activating different pathways depending if the complex is formed or not
How does heparan sulphate proglycan co-receptor work?
They have no catalytic function binds to long isoforms of VEGF
How do we account for the many different effects of VEGF signalling cascade
Proteins bind to the SH2 domain and depending on what TYR gets hosphorylated different processes will be modulated.
TYR1175 survival and proliferation
TYR 951 metastasis and vascular permeability
What’s degradation of ECM by? What cell do they come from? What is it controlled by?
It’s by zinc dependent enzymes,endothelial cells or tumour or stromal.
TIMP
What is the main protein involved in the loosening of cell to cell junctions? And what is the effect
VE cadherin, it increases permeability by VEGFR dissociating from VE cadherin when VEGF binds
How do cells sprout and what determines if the cells are tip or stalk?
They grow toward the chemotatic gradient of VEGF, the cells that have notch activation are stalk cells while the notch inactivation are the tip cells
How is lumen formed?
The vacuoles will join
What is anastomosis?
Joining of many capillaries
Outline the steps in vessel maturation
VEGF recruits myeloid cells that support maturation
The endothelial cells will stabilize their junction
Tip cells produce PDGF-BB that will recruit the pericyte
Pericyte will adhere to endothelial cells and further proliferation can’t occur
The vessels are mature
Non sprouting angiogenesis, what are two ways?
Vasculogenesis-endothelial progenitor cells recruited to tumour and they differentiate to mature tumour endothelial cells
Or cancer stem cells can differentiate into them
Vasculogenesis mimicry- The tumour cells will differentiate into them
What other ways can tumours vascularize?
Through vessel co-option where the tumours grow alongside of capillares.
Or intussusceptive microvascular growth- where the vessel lumens part and the vessels enlarge
What are the functional and structural abnormalities found in tumour vascularization?
Erratic blood flow, low oxygen level, increased IF pressure, more leakage, disorganized, less pericyte coverage, enlarged diameter, destabilization junctions, disorganized
What are the anti-cancer strategies when targetting angiogenesis and what is their mechanism and consequences?
Vascular disruption-Shuts down selectively established tumor vessels
Intermitent dosage
hemorrhage necrosis
Induces necrosis of tumour cells
Anti-angiogenesis- Stops new vessels from forming
Continuos dosage
Give examples of drugs used when targetting angiogenesis
Bevasizumab- antibody against VEGF A neutralizing
VEGF trap- soluble VEGF
Iressa- blocks EGFR and productionof VEGF, BFGF
Sunitinib-small molecules of VEGFR signalling inhibitors
Examples of angiogenesis inhibitor stimulation
Tamoxifen- induces endostatin
How is renal cell cancer treated?
VHL is often degraded in this type of cancer leading to enhanced activation of VEGF, using anti-angiogenic strategy has good progression free disease and overall survival
What are the problems with using anti-angiogenic treatment?
Tumour response is temporary usually because of the microenvironment reccurence is very common in many different ways such as pro-angiogenic inflammatory response, recruiting pericyte, increased invasiveness.
Toxicity- such as hypertension
Treatment resistance
What are possible ways to mitigate these problems? And how does this optimize treatment
Using combination therapy, when using chem- or radiotherapy along with administering the anti angiogenic drug not only the endothelial cells will be targetted but also cancer cells. Also when using this AA drug it will normalize the vessels which will make them less resistance to other types of therapy.
What is “window of opportunity”?
It is referring to the timing of the dosage of anti-angiogenic drug, it can’t be for too long or there will be excessive pruning and enhanced angiogenesis and this will make it more resistant to chemo or radio-therapy and it can’t be too little or it won’t be effective in sensitizing the tumour, so it’s referring to optimal dosage that improves delivery.
What’s the difference between predictive and prognostic biomarkers?
Predictive is looking at the response of the patient after treatment that correlates wtih clinical response.
Prognostic is seeing the overall outcome of the diease based on that biomarker
Are there any angiogenesis biomarkers and what are potential ones?
No, but VEGF isomers are potential ones.
What are some examples of vascular distruption drugs?
Tubulin binding agents(CA4P) and integrin antagonist
What are the problems with CPA4 or VDA? And what are ways to optimize treatment?
The tumour rim is resistant. VDA induces hypoxia, vessel loss and collapse, permeability macrophage recruitment. Combination treatments are optimal because target different cell populations and makes vessels more sensitive to VDA after other treatment, even using inhibitors with macrophage recruitment makes it more effective.
