Tumour angiogenesis, invasion and metastasis Flashcards
What are the characterisitcs of malignant tumours?
Unlimited growth as long as an adequate blood supply is available
Invasiveness - migration of tumour cells into the surrounding stroma where they are free to disseminate via vascular or lymphatic channels to distant organs
Metastatis - spread of tumour cells from the primary site to form secondary tumours at other sites in the body
What are the steps in cancer progression?
What is angiogenesis?
= formation of new blood vessels from pre-existing vessels
How do tumours aquire their own blood supply?
a) Small tumour eventually gets to a large enough size when delivery of oxygen and nutrients from nearby capillaries becomes limiting
b) Tumour switches on expression of angiogenic genes/factors that initiate new blood vessel growth
c) New network of blood vessels grows in and around the tumour (tumour angiogenesis) including the delivery of oxygen and nutrients that allows it to increase growth and provides a route for cells to shed off and spread
What is the switch that causes the increase in growth factors released from the tumour?
The tumour starts to expand and proliferate so it gets to a certain size and distance away from the blood vessel, so diminished oxygen supply = hypoxia
- Hypoxia = low oxygen tension
- Strong stimulus for tumour angiogenesis
Activates transcription of genes involved in angiogenesis, tumour cell migration and metastasis
What are angiogenic factors?
Some tumour cells produce factors that stimulate the directional growth of endothelial cells:
- Vascular endothelial growth factor
- Fibroblast growth factor 2
- Placental growth factor
- Angiopoietin 2
These factors are secreted by tumour cells or are stored bound to components of the extracellular matrix and can be released by enzymes called matrix metalloproteinases
How do Ang-2 and VEGF go from tumour cells to the blood vessel?
Ang-2 and VEGF will be released from tumour cells and will bind to receptors on the endothelial cell of the blood vessel
What is VEGF signalling?
What are the Mechanisms of tumour cell motility and invasion?
- Increased mechanical pressure caused by rapid proliferation
- Increased motility of the malignant cells
- Increased production of degradative enzymes of both tumour cells and stromal cells
What is the epithelial-mesenchymal transition?
In the transition you will lose:
- Epithelial shape and cell polarity
- Cytokeratin intermediate filament expression
- Epithelial adherents junction protein
In the transition you will acquire:
- Fibroblast-like shape and motility
- Invasiveness
- Vimentin intermediate filament expression
- Mesenchymal gene expression
- Protease secretion
What are E-cadherins?
= homotypic adhesion molecule
- Forms a dimer with each other
- Bind to B-catenin on intracellular domains
- Inhibits invasiveness
What is the difference in a normal cell with E-cadherin’s and a cell where there is a loss of E-cadherin’s?
What do inactive pro-uPA do and where does it come from?
The tumour cells also become more motile and more invasive as they release enzymes that allow them to invade the extracellular matrix
Stromal cells will release factors like angiogenic factors, growth factors, cytokines and protease
- Inactive pro-uPA will be released by the stromal cell and then bind to receptor on cancer cell
- Inactive is converted to active from of uPA
- Which then activates plasminogen to plasmin
- Plasmin can go onto activate matrix metalloproteinases (MMPs) = permits invasion by degrading extracellular matrix and releasing matrix-bound angiogenic factors like TGF-B1
What are the steps involved in cancer dissemination?
(spreading)
What determines the pattern of tumour spread? - hypothesis
Specific adhesions between tumour cells and endothelial cells in the target organ, creating a favourable environment in the target organ for colonisation = seed and soil hypothesis
Anatomical considerations - close by
