Tumour angiogenesis Flashcards
What is the result of the reduced blood vessel density seen in cancer?
The size to which the tumour can grow is limited by the O2 barrier of diffusion, as blood vessel desnity is decreased we see a change in pH and eventually hypoxic injury which can lead to cell death
What are the mechanisms of cell death from hypoxia?
Necrosis or p53 mediated apoptosis
How do cancer cells adapt to hypoxia?
They will try to drop their mitochondrial activity (which requires O2) and instead use increased amounts of glycolysis and glutamine to replace fatty acids
What are the drivers of metabolic changes which occur in cancer cells?
Environmental causes and different cell requirements
Build up of biomass
Ribosomal biogenesis
What is the Warburg effect?
This refers to the fact that many cancer cells use higher rates of glycolysis in favour of oxidative phosphorylation even in the presence of sufficient O2
What is glutaminolysis?
This refers to increased cellular uptake of glutamine and its catabolism in cells
This is a common metabolic shift seen in cancer cells which provides and alternative input of carbon for the TCA cycle to act as a biosynthesis hub
This supports the production of amino acids, nucleic acids and fatty acids in cancer cells
This also helps to control the redox state in cancer cells (through glutathione synthesis)
This ultimately results in tumour cells becoming addicted to glutamine
What are the consequences of tissue hypoxia?
There is new vessel formation through hypoxia inducible factor which leads to the expression of vascular endothelial growth factor
What is the angiogenic switch?
This refers to a process which allows the formation of new blood vessels within tumours and occurs early in tumour development
It is aprocess that activates quiescent endothelial cells causing them to enter into a cell-biological program that allows them to construct new blood vessels
What are the processes of vessel formation?
Vasculogenesis which is de novo origin of endothelial cells from stem cells (haemangioblasts) and their assembly into vessels
Angiogenesis where there is sprouting of new blood vessels from pre-existing vessels, this involves the actions of previously quiescent blood endothelial cells
Lymphangiogenesis where there is formation of new lymphatic vessels via proliferation and assembly of lymphatic endothelial cells
What is the continuum of vessel formation?
Vasculogenesis results in the formation of mature vessels, these may respond to angiogenesis and produce more mature vessles or they may regress
What are the cellular steps in angiogenesis?
An angiogenic factor such as VEGF signal to a pre-existing blood vessel and proteases break down the blood vessel basement membrane
Endothelial cells then migrate in response to the signalling molecule to produce the beginnings of a vascular sprout there is then endothelial cell proliferation resulting in sprout elongation, this is followed by capillary morphogenesis leading to formation of a lumen in the angiogenic sprout
Vascular maturation follows where there is vascular pruning and recruitment of smooth muscle cells and pericytes there is also formation of endothelial cell junctions
What are the features of tumour vasculature?
It is chaotic and tortuous, defective and non-contiguous (holey), it is also mosaic (mixed with cancer cells) allowing shedding of numerous cancer cells in to circulation daily, similarly vascular mimicry is when cancer cells form the blood vessels
What are the enhancers of angiogenesis?
VEGF, BFGF, Angiogenin, PDGF, IL-8 and angipoietin
What is the simplistic view of the angiogenic switch?
Tumour cells begin expressing VEGF and activating normal endothelial cells
What is the more realistic view of the angiogenic switch?
There are multiple cell types which contribute to angiogenesis including tumour cells, macrophages and fibroblasts
What is VEGF-A?
This is a ligand produced by tumour cells, TAMs and CAFs which have a receptors VEGF-R1&2 on blood endothelial cells and is capable of inducing proliferation and migration of endothelial cells
What is PDGF?
This is a ligand produced by blood endothelial cells which is recognised by PDGFR on pericytes which can induce vascular support
What is Ang1?
This is a ligand produced by pericytes which bind to the Tie2 receptor on blood endothelial cells and maintains vessel integrity
What is Ang2?
This is a ligand produced by pericytes which bind to the Tie2 receptor on blood endothelial cells and maintains vessel integrity
What are the different functions of VEGFRs?
VEGFR1 binds VEGFA and B and induces angiogenesis
VEGFR2 binds VEGFA,C and D and induces both angiogenesis and lymphogenesis
VEGFR3 binds VEGF C and D and induces Lymphangiogenesis
What are the additional signalling pathways which function in angiogenesis?
Notch
Neuropilin
Robo
Ephrin
What are the endogenous inhibitors of angiogenesis-1?
Endostatin and Thrombospondin 1 and 3
What are the affects of thrombospondin-1?
This makes cells express FasL
What are the endogenous inhibitors of angiogenesis-2?
Angiostatin
TIMP-2
Why does angiogenesis seem like a good target for cancer therapy?
Cancerous tissues would be targeted while most healthy tissues would not be
Angiogenic signals and cell surface receptors may provide points for intervention
Endothelial cells are stable targets as there is a lack of genetic instability
What is the effect of VEGF pathway inhibitors on cancer?
This may stop the proliferation of ne vessels however established tumour vessels are relatively insensitive of VEGF pathway inhibition
What is Avastin?
This is an anti-VEGF antibody which is an example of a therapy which aims to inhibit tumour associated vasculature by anti-angiogenic drugs
What are the mechanisms of resistance cancer cells have to VEGF pathway inhibitors?
They shift to and upregualte other pro-angiogenic signalling circuits
What are the molecular differences between normal and tumour vasculature?
Neoplastic endothelial cells express antigens and transcription factors that normal vessels do not- this may provide therapeutic targets against cancer
This includes the new strategies where toxic nanoparticles are delivered to the tumour through its defective vasculature and are then activated by a laser
What are the approaches to inhibit tumour angiogenesis?
VEGF inhibitors, anti-VEGF antibodies
VEGFR inhibitors
Inhibitors of metalloproteinase enzymes
Inhibition of pericytes
Targeting antigens expressed only on tumour vessels
Delivery of nanoparticles through defective vessels
