Targeting Angiogenesis in Cancer Therapy Flashcards
What is angiogenesis?
Recruitment of endothelial cells from existing blood vessels
What is vasculogenesis?
Activation of endothelial cell precursors + new blood vessels
What happens when the tumour can’t get any bigger?
Gets to point where can’t grow = surrounding cells aren’t providing nutrients
= need its own blood supply
= can break off go to other places (metastases)
What is the growth?
Tumours can grow to approx. 1-2mm without adequate blood supply
= angiogenesis rate limiting step for growth + metastasis
Good correlation between micro vessel density in tumour + development of metastases + patient survival
Describe tumour angiogenesis
Tumours <2mm receive oxygen + nutrients by diffusion from host vasculature
Large tumours require new vessel network
Tumour secretes angiogenic factors that stimulate migration, proliferation + neovessel formation by endothelial cells in adjacent established vessels
Newly vascularised tumour no longer relies solely on diffusion from host vasculature = facilitating progressive growth
Describe the angiogenic process
Tumour release pro-angiogenic factors, such as vascular endothelial growth factor (VEGF)
VEGF binds to receptors on endothelial cells of pre-existing blood vessels = activation
Interaction leads to secretion + activation of proteolytic enzymes
Degradation of ECM allows activated proliferating endothelial cells to migrate towards tumour
Endothelial cells deposit a new basement membrane + secrete growth factors, such as platelet-derived growth factor (PDGF), which attract supporting cells to stabilise new vessel
Describe VEGF + FGF
Angiogenic regulating growth factors
Production low in normal cells
Upregulated in tumours
VEGF activates transmembrane receptors present on endothelial cells
FGF more widespread
Describe VEGF ligand
Express angiogenic effects by binding to specific primary VEGF receptors on endothelial cell surface
Describe function of VEGF-2
Important receptor in tumour angiogenesis
Mediates majority of VEGF angiogenic effects
Describe anti-angiogenic strategies
Inhibition of endothelial cell activation = Avastin
Blocking growth factor receptor signalling = Sunitinib
Inhibition of matrix metalloproteinases (MMPi) = Batimastat
What targets VEGF in NSCLC?
Tyrosine kinase inhibitors (TKI)
How does Avastin work?
Binds with VEGF
= starves tumour of nutrients
How does Sunitinib work?
Block VEGF signalling
How does immunotherapy work?
Aim to induce an adaptive immune response to a cancer antigen
Describe immune checkpoint
T cells have checkpoints (PD-1)
= protect against auto-immunity + excessive immune response to an infection
Tumours adopt these immune inhibitory mechanisms to escape immune elimination
What do immune checkpoint inhibitors do?
Reverse “off-switch” for immune system adopted by tumours
Reduces T cell responses by inducing downstream inhibitory signalling + competitively binds with ligand on surface of antigen presenting cells
What is PD-1/PD-L1?
Immune inhibitory receptors on surface of T cells which binds to PD-L1 on surface of tumour cells
