Tumour Angiogenesis, Invasion And Metastasis Flashcards
What are the characteristics of malignant tumours?
Unlimited growth as long as adequate blood supply available
Invasiveness - tumour cells migrate to surrounding stroma and move through vascular/lymphatic channels to distant organs
Metastasis - spread of secondary tumours from primary site
What are the stages in cancer progressions to metastasis?
Transformation - mutagenic and epigenetic changes followed by clonal selection
Angiogenesis - new blood vessel formation overcoming limitation of hypoxia
Motility and invasion - epithelial to mesenchymal transition
Metastasis - colonise target organs
define angiogenesis
Formation of new blood vessels from PRE-EXISTING BLOOD VESSELS
What is vascularogenesis?
Formation of new blood vessels from its progenitors
What are the types of angiogenesis?
Developmental vasculogenesis e.g. for organ growth
Normal angiogenesis e.g. for wound repair, placenta during pregnancy
Pathological angiogenesis - tumour angiogenesis, ocular and inflammatory disorders
How big can tumours grow without own blood supply (own vessles infiltrating tumour)
1-2 mm
Describe the stages and process of tumour angiogenesis?
Small tumour gets large enough when delivery of oxygen from nearby capillaries is limiting
Tumour switches on angiogenic genes to release angiogenic factors that initiate new blood vessel growth
New network of blood vessels grow in and around tumour increasing delivery of oxygen and nutrients
What functions do the new blood vessels in the tumour have?
Provide oxygen and nutrients fro growth
Provides route for cells to shed off and enter circulation to spread
What causes tumour angiogenesis (stimulus)?
Hypoxia
How does increasing tumour size affect hypoxia?
Cells in tumour further away from capillaries becomes hypoxic (further distance from capillaries increase hypoxia)
Which target genes are activated for tumour angiogenesis once hypoxia stimulus is detected? !!!
VEGF - vascular endothelial growth factor - most imp growth factor for new blood vessel formation as its a stimulus for endothelial migration
GLUT-1 - glucose transporter 1 - for glucose uptake
More involved in invasion and metastasis
u-PAR - urokinase plasminogen activator receptor
PAI-1 - plasminogen activator inhibitor 1
name a few angiogenic factors (not genes that code for them) secreted by the tumour that stimulate direction growth of endothelial cells? !!!!
VEGF - vascular endothelial growth facor
FGF 2 - fibroblast growth factor 2
PIGF - placental growth factor
Ang 2 - angiopoietin 2
Where do the angiogenic factors that are secreted go?
Stored in extracellular matrix and released by enzymes called matrix metalloproteinases (MATRIX METALLOPROTEINASE 2 - MMP-2)
Describe the VEGF signalling stages in detail?!
VEGF binds to VEGF R2 on endothelial cells
VEGF/VEGF R2 dimerises at plasma membrane which recruits cofactors that activate major signal transduction pathway
Cell survivial, vascular permeability, gene expression and cell proliferation all activated by VEGF - processes all part of angiogenesis
What do all the different factors released by tumours do?
Endothelial proliferation + migration (all angiogenic factors cause this), and invasion(MMP2 causes this) (done by diff factors)
What are the 3 mechanisms for tumour cell motility and invasion?
Increased mechanical pressure due to rapid cellular proliferation
Increased motility of malignant cells (from epithelial to mesenchymal tissues allows cells to now move)
Increased production of degradative enzymes by tumour and stromal cells
What do tumour cells lose(downregulate) in epithelial mesenchymal transition (EMT)?
Downregulate genes that make epithelial markers such as e cadherin, b catenin, claudin 1
ultimately causing loss of:
Epithelial shape and cell polarity (loss of b catetnin and claudin 1)
Cytokeratin intermediate filament expression (required for structure of epthelial cell shape)
Epithelila adherns junction protein (e cadherin)