Angiogenesis and metastasis Flashcards
What is metastasis?
The ability of cancer cells to escape from the primary tumour via the blood and lymphatic system and to grow in a secondary site.
What is the tumour microenvironment?
Cancer cells in primary tumours are surrounded by a complex microenvironment which compromises of numerous cells including endothelial cells of the blood and lymphatic circulation, stromal fibroblasts and a variety of bone marrow derived cells.
What is the metastatic cascade?
Primary tumour growth
Angiogenesis
Detachment and invasion into the surrounding tissue towards the vessle
Intravasation into lympathics/ capillaries
Survival in the circulation
Arrest in new and secondary organ capillaries
Extravasation into the secondary tissue
Establishment of the microenvironment – death, dormant, proliferating
What do tumour cells need to do in order to grow?
They need to attract new blood vessels to provide necessary energy.
They grow more quickly than normal cells and outgrow their source of oxygen and nutrients.
What is angiogenesis?
The growth of new blood vessels.
The formation, maturation and differentiation of blood vessels from pre-existing vessles.
What conditions is neo-angiogenesis driven by?
Hypoxic conditions Not enough oxygen 1mm tumour HIF1alpha transcription factor Expression of VEGF Bings to VEGFR on endothelial cells
What is VEGF-VEGFR
Vascular endothelial growth factor family members and receptors.
Activation of VEGFR mediates proliferation, vascular permeability, cell migration and cell survival which leads to angiogenesis.
VEGFR signalling via RAS/MEK/ERK pathway induces gene expression and results in cell proliferation.
Angiogenesis can be inhibited by small molecule VEGFR inhibitors which block these pathways.
What is tumour angiogenesis?
Mediated by epithelial cells it is a process in which a cell has acquired genetic alterations and allow unlimited growth and escape from apoptosis and a small tumour is formed.
When the tumour reaches a few mm and the oxygen supply is insufficient tumour cells undergo and angiogenesis switch.
This results in production and release of growth factors into surrounding tissues. These growth factors then bind to receptors on the epithelial cells in nearby tissues and in nearby vessels.
Pericytes that stabilise the vessel detach and vessel dilation occurs and the activated endothelial cells start to produce proteases that degrade the basal membrane and the extracellular matrix.
The epithelial cells start to migrate and proliferate into the growth factor gradient and forms a new vascular structure.
Matrix proteins are then deposited and the new vessel is stabilised by pericytes to form a functional and mature blood vessel.
Tumour cells can continue to grow and metastasis formation is facilitated since tumour cells have easy access to the circulation.
What is angiogenesis controlled by?
Activators and inhibitors.
Increased angiogenesis correlates with worse prognosis
What are anti-angiogenetic therapies in cancer?
Monoclonal antibodies,
Decoy receptors
Receptor kinase inhibitors
What is bevacizumab?
Monoclonal anti-VEGF-A antibody, which neutralises VEGF-A/
Cancers are highly dependent on the induction of angiogenesis by VEGF, where the best responders to anti-VEGF agents. They include colorectal and renal cell carcinoma.
Cancers relying on angiogenic factors other than VEGF are less susceptible to anti-VEGF agents.
There is rapid resistance to bevacizumab
What are the resistance mechanisms to angiogenesis inhibition?
Metabolic adaptation
Revascularisation by expression of alternative angiogenic factors
Co-option of normal peritumoral blood vessels and vascular mimicry.
Blood flow alterations owing to vessel pruning and normalisation can improve blood flow.
Anti-angiogenic therapy induces vascular regression which leads to intratumoral hypoxia and selection of more invasive cancer cells that are resistant to anti-angiogenetic therapy.
What must a carcinoma cell do to acquire motility?
Change their phenotype from a more epithelial to mesenchymal phenotype.
How can cancer cells enter circulation?
Transmigrating either paracellularly through endothelial cell junctions by remodeling of the cell-cell junctions between endothelial cells necessary.
Transcellularly through the EC body – rapid cytoskeletal and membrane remodelling, which creates a transitory pore like structure for the cancer cell to cross the EC.
How do cancers survive in circulation?
Interaction with platelets, lymphocytes
Sheer stress
Anoikis
